VCV000288909.15 - ClinVar

NM_000067.3(CA2):c.232+1G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000067.3(CA2):c.232+1G>A

Variation ID: 288909 Accession: VCV000288909.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q21.2 8: 85465470 (GRCh38) [ NCBI UCSC ] 8: 86377699 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 22, 2016	Apr 6, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000067.3:c.232+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001293675.2:c.48+1G>A		splice donor
NC_000008.11:g.85465470G>A
NC_000008.10:g.86377699G>A
NG_007287.1:g.6454G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS2DS, G-A, +1

Canonical SPDI

NC_000008.11:85465469:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA4796434 OMIM: 611492.0006 dbSNP: rs573750741 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CA2		-	-	GRCh38 GRCh37	150	205

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Osteopetrosis with renal tubular acidosis	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000373455.11
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 10, 2022	RCV000726247.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 15, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000343155.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CA2 Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Osteopetrosis with renal tubular acidosis Affected status: yes Allele origin: germline	3billion Accession: SCV002058668.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Comment: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are … (more) Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000288909). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Aggressive behavior (present) , Attention deficit hyperactivity disorder (present) , Cerebral calcification (present) , Global developmental delay (present) , Metabolic acidosis (present) , Osteopetrosis (present) … (more) Aggressive behavior (present) , Attention deficit hyperactivity disorder (present) , Cerebral calcification (present) , Global developmental delay (present) , Metabolic acidosis (present) , Osteopetrosis (present) , Severe failure to thrive (present) (less)
Pathogenic (Jan 10, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001769535.3 First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023	Comment: Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is … (more) Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16382316, 31130284, 25525159, 1301935, 25099932, 25674028, 28509178, 27717089, 15300855, 7959703, 29302074, 29620724, 30510438, 30109220, 32552793) (less)
Pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Osteopetrosis with renal tubular acidosis Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004801217.2 First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024
Pathogenic (Jun 08, 2015)	no assertion criteria provided Method: clinical testing	Osteopetrosis with renal tubular acidosis (Autosomal recessive inheritance) Affected status: yes, unknown Allele origin: germline	Baylor Genetics Accession: SCV000328860.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 1301935 Comment: Our laboratory reported three molecular diagnoses in CA2 (NM_000067.2, c.232+1G>A), MCCC2 (NM_022132.4, c.1015G>A), and SPG11 (NM_025137.3, c.6100C>T) in one individual with clinical features of global … (more) Our laboratory reported three molecular diagnoses in CA2 (NM_000067.2, c.232+1G>A), MCCC2 (NM_022132.4, c.1015G>A), and SPG11 (NM_025137.3, c.6100C>T) in one individual with clinical features of global developmental delay, developmental regression, autistic features, intellectual disability, hypotonia, ataxia, dysmorphic features, short stature, microcephaly, hyperextensibility, failure to thrive, structural brain abnormalities, skeletal abnormalities, and limb malformation. The CA2 variant has been previously reported as disease-causing [PMID 1301935]. Heterozygotes would be expected to be asymptomatic carriers. (less) Observation 1: Number of individuals with the variant: 1 Family history: yes Age: 20-29 years Sex: female Geographic origin: Middle East Observation 2: Number of individuals with the variant: 1 Age: 10-19 years Sex: male Geographic origin: Qatar
Pathogenic (Sep 18, 2017)	no assertion criteria provided Method: clinical testing	Osteopetrosis with renal tubular acidosis Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000746078.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Aug 25, 2019)	no assertion criteria provided Method: clinical testing	Osteopetrosis with renal tubular acidosis Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001132952.1 First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020
Pathogenic (Jan 01, 1992)	no assertion criteria provided Method: literature only	OSTEOPETROSIS, AUTOSOMAL RECESSIVE 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021116.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 13, 2021	Publications: PubMed (1) PubMed: 1301935 Comment on evidence: Hu et al. (1992) pointed out that of the 39 reported cases of carbonic anhydrase deficiency syndrome (259730), 72% were patients from North Africa and … (more) Hu et al. (1992) pointed out that of the 39 reported cases of carbonic anhydrase deficiency syndrome (259730), 72% were patients from North Africa and the Middle East countries, most, if not all, of whom were of Arab descent. They showed that members of 6 unrelated Arab kindreds were in 5 instances homozygous and in 1 instance heterozygous for a novel splice junction at the 5-prime end of intron 2. Called the 'Arabic mutation,' it introduces a new Sau3A1 restriction site useful in PCR-based diagnosis, carrier detection, and prenatal diagnosis. The presence of mental retardation and relative infrequency of skeletal fractures distinguish the clinical course of patients with the Arabic mutation from that of American and Belgian patients with the H107Y mutation (611492.0004). (less)

Comment:

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000288909). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16382316, 31130284, 25525159, 1301935, 25099932, 25674028, 28509178, 27717089, 15300855, 7959703, 29302074, 29620724, 30510438, 30109220, 32552793)

Comment:

Our laboratory reported three molecular diagnoses in CA2 (NM_000067.2, c.232+1G>A), MCCC2 (NM_022132.4, c.1015G>A), and SPG11 (NM_025137.3, c.6100C>T) in one individual with clinical features of global developmental delay, developmental regression, autistic features, intellectual disability, hypotonia, ataxia, dysmorphic features, short stature, microcephaly, hyperextensibility, failure to thrive, structural brain abnormalities, skeletal abnormalities, and limb malformation. The CA2 variant has been previously reported as disease-causing [PMID 1301935]. Heterozygotes would be expected to be asymptomatic carriers.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A splice junction mutation in intron 2 of the carbonic anhydrase II gene of osteopetrosis patients from Arabic countries.	Hu PY	Human mutation	1992	PMID: 1301935
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CA2	-	-	-	-

Text-mined citations for rs573750741 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_000067.3(CA2):c.232+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs573750741 ...