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NM_001378.3(DYNC1I2):c.740A>G (p.Tyr247Cys) AND Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 28, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001254719.2

Allele description [Variation Report for NM_001378.3(DYNC1I2):c.740A>G (p.Tyr247Cys)]

NM_001378.3(DYNC1I2):c.740A>G (p.Tyr247Cys)

Gene:
DYNC1I2:dynein cytoplasmic 1 intermediate chain 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q31.1
Genomic location:
Preferred name:
NM_001378.3(DYNC1I2):c.740A>G (p.Tyr247Cys)
HGVS:
  • NC_000002.12:g.171726051A>G
  • NM_001271785.2:c.740A>G
  • NM_001271786.2:c.716A>G
  • NM_001271787.2:c.716A>G
  • NM_001271788.2:c.662A>G
  • NM_001271789.2:c.662A>G
  • NM_001271790.2:c.662A>G
  • NM_001320882.2:c.722A>G
  • NM_001320883.2:c.722A>G
  • NM_001320884.2:c.662A>G
  • NM_001378.3:c.740A>GMANE SELECT
  • NP_001258714.1:p.Tyr247Cys
  • NP_001258715.1:p.Tyr239Cys
  • NP_001258716.1:p.Tyr239Cys
  • NP_001258717.1:p.Tyr221Cys
  • NP_001258718.1:p.Tyr221Cys
  • NP_001258719.1:p.Tyr221Cys
  • NP_001307811.1:p.Tyr241Cys
  • NP_001307812.1:p.Tyr241Cys
  • NP_001307813.1:p.Tyr221Cys
  • NP_001369.1:p.Tyr247Cys
  • NC_000002.11:g.172582561A>G
  • NM_001378.2:c.740A>G
  • NM_001378.3(DYNC1I2):c.740A>GMANE SELECT
  • p.Tyr247Cys
Protein change:
Y221C; TYR247CYS
Links:
OMIM: 603331.0002; dbSNP: rs752940799
NCBI 1000 Genomes Browser:
rs752940799
Molecular consequence:
  • NM_001271785.2:c.740A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001271786.2:c.716A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001271787.2:c.716A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001271788.2:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001271789.2:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001271790.2:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320882.2:c.722A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320883.2:c.722A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320884.2:c.662A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001378.3:c.740A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA)
Identifiers:
MONDO: MONDO:0060490; MedGen: C4479566; OMIM: 617481

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001430794Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(May 28, 2020) 		germlineresearch

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features.

Ansar M, Ullah F, Paracha SA, Adams DJ, Lai A, Pais L, Iwaszkiewicz J, Millan F, Sarwar MT, Agha Z, Shah SF, Qaisar AA, Falconnet E, Zoete V, Ranza E, Makrythanasis P, Santoni FA, Ahmed J, Katsanis N, Walsh C, Davis EE, Antonarakis SE.

Am J Hum Genet. 2019 Jun 6;104(6):1073-1087. doi: 10.1016/j.ajhg.2019.04.002. Epub 2019 May 9.

PubMed [citation]
PMID:
31079899
PMCID:
PMC6556908

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001430794.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (2)

Description

The heterozygous p.Tyr247Cys variant in DYNC1I2 was identified by our study, in the compound heterozygous state, along with another pathogenic variant, in an individual with neurodevelopmental disorder with microcephaly and structural brain anomalies (NEDMIBA) (PMID: 31079899). This variant has also been reported in an additional individual with NEDMIBA, and has been identified in 0.048% (4/8316) by Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752940799). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 635400). The presence of this variant in combination with reported pathogenic variants and in 2 individuals with NEDMIBA increases the likelihood that the p.Tyr247Cys variant is pathogenic (PMID: 31079899). Animal models in zebrafish have shown that this variant causes NEDMIBA (PMID: 31079899). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for NEDMIBA in an autosomal recessive manner based on zebrafish models and multiple occurrences confirmed in trans with pathogenic variants. ACMG/AMP Criteria applied: PM3_Strong, PS3, PP3 (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Mar 30, 2024