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

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 2, 2019
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000786849.3

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 and structural brain anomalies
Identifiers:
MONDO: MONDO:0032779; MedGen: C5193123; OMIM: 618492

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000925746OMIM
no assertion criteria provided
Pathogenic
(Jul 2, 2019) 		germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

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

Details of each submission

From OMIM, SCV000925746.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In a 3-year-old boy, born of unrelated parents of European (father) and Ashkenazi Jewish (mother) descent, with neurodevelopmental disorder with microcephaly and structural brain anomalies (NEDMIBA; 618492), Ansar et al. (2019) identified a heterozygous maternally inherited c.740A-G transition (c.740A-G, NM_001378.2) in the DYNC1I2 gene, resulting in a tyr247-to-cys (Y247C) substitution at a highly conserved residue, and a heterozygous paternally inherited 374-kb deletion on chromosome 2q31 that encompassed 4 genes, including DCAF17 (612515), CYBRD1 (605745), DYNC1I2, and SLC25A12 (603667). The variants were found by a combination of chromosomal microarray analysis and whole-exome sequencing. The Y247C variant was found at a low frequency in the gnomAD database (1.8 x 10(-5)), only in heterozygosity in 4 individuals of Ashkenazi Jewish descent. The findings were thus consistent with a recessive cause of the phenotype. An unrelated patient (family 3) of Eastern European/Russian descent with a similar phenotype was found to be compound heterozygous for Y247C and a c.868C-T transition, resulting in a gln290-to-ter (Q290X; 603331.0003) substitution. These variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The Q290X variant was not found in the gnomAD database. Molecular modeling predicted that the Y247C variant may interfere with dynein protein interactions. Studies of patient cells were not performed, but expression of homologous mutations created on a different human DYNC1I2 isoform in dync1i2a-null zebrafish failed to rescue the phenotype of decreased head circumference, indicating that both mutations result in a loss of function.

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

Last Updated: Mar 30, 2024