rs201177183
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_017721.5(CC2D1A):c.1192G>A(p.Val398Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,612,998 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017721.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000598 AC: 91AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000340 AC: 84AN: 246804Hom.: 0 AF XY: 0.000312 AC XY: 42AN XY: 134576
GnomAD4 exome AF: 0.000340 AC: 497AN: 1460716Hom.: 1 Cov.: 34 AF XY: 0.000310 AC XY: 225AN XY: 726648
GnomAD4 genome AF: 0.000598 AC: 91AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47AN XY: 74448
ClinVar
Submissions by phenotype
Intellectual disability, autosomal recessive 3 Uncertain:2
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not provided Uncertain:1Benign:1
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not specified Uncertain:1
Variant summary: CC2D1A c.1192G>A (p.Val398Met) results in a conservative amino acid change located in the third DM14 domain (IPR006608) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 246804 control chromosomes, predominantly at a frequency of 0.0021 within the African or African-American subpopulation in the gnomAD database. The relatively high subpopulation frequency might suggest a benign role for this variant. To our knowledge, no occurrence of c.1192G>A in individuals affected with Intellectual Disability 3 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=3) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Inborn genetic diseases Uncertain:1
The p.V398M variant (also known as c.1192G>A), located in coding exon 11 of the CC2D1A gene, results from a G to A substitution at nucleotide position 1192. The valine at codon 398 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at