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
Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00034 ( 1 hom. )
Consequence
CC2D1A
NM_017721.5 missense
NM_017721.5 missense
Scores
3
12
4
Clinical Significance
Conservation
PhyloP100: 8.78
Genes affected
CC2D1A (HGNC:30237): (coiled-coil and C2 domain containing 1A) This gene encodes a transcriptional repressor that binds to a conserved 14-bp 5'-repressor element and regulates expression of the 5-hydroxytryptamine (serotonin) receptor 1A gene in neuronal cells. The DNA binding and transcriptional repressor activities of the protein are inhibited by calcium. A mutation in this gene results in a nonsyndromic form of cognitive disability (MRT3). [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.14174417).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CC2D1A | NM_017721.5 | c.1192G>A | p.Val398Met | missense_variant | 11/29 | ENST00000318003.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CC2D1A | ENST00000318003.11 | c.1192G>A | p.Val398Met | missense_variant | 11/29 | 1 | NM_017721.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000598 AC: 91AN: 152164Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000340 AC: 84AN: 246804Hom.: 0 AF XY: 0.000312 AC XY: 42AN XY: 134576
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GnomAD4 exome AF: 0.000340 AC: 497AN: 1460716Hom.: 1 Cov.: 34 AF XY: 0.000310 AC XY: 225AN XY: 726648
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GnomAD4 genome ? AF: 0.000598 AC: 91AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.000631 AC XY: 47AN XY: 74448
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability, autosomal recessive 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 08, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 16, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 21, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2023 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 01, 2019 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at