rs201177183

Positions:

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 8.78

Variant links:

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]

CC2D1A links:

Genome browser will be placed here

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 linkuse as main transcript	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 linkuse as main transcript	c.1192G>A	p.Val398Met	missense_variant	11/29	1	NM_017721.5	P3	Q6P1N0-1

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000340

AC:

AN:

246804

Hom.:

AF XY:

0.000312

AC XY:

AN XY:

134576

show subpopulations

Gnomad AFR exome

AF:

0.00212

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000341

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000340

AC:

497

AN:

1460716

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

225

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000378

Gnomad4 NFE exome

AF:

0.000336

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000598

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000315

Hom.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00224

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.000389

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000534

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	Labcorp Genetics (formerly Invitae), Labcorp	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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.7

D;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.68

MVP

0.55

MPC

0.81

ClinPred

0.13

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over