rs191830054

chr19-13919829-A-Gchr19-13919829-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_017721.5(CC2D1A):c.1234A>G(p.Ile412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,603,876 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I412M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 5 hom. )

Consequence

CC2D1A
NM_017721.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 3.18

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010265142).

BP6

Variant 19-13919829-A-G is Benign according to our data. Variant chr19-13919829-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210590.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D1A	NM_017721.5 linkuse as main transcript	c.1234A>G	p.Ile412Val	missense_variant	12/29	ENST00000318003.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D1A	ENST00000318003.11 linkuse as main transcript	c.1234A>G	p.Ile412Val	missense_variant	12/29	1	NM_017721.5	P3	Q6P1N0-1

Frequencies

GnomAD3 genomes

AF:

0.00242

AC:

368

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00238

AC:

590

AN:

248050

Hom.:

AF XY:

0.00237

AC XY:

319

AN XY:

134670

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00405

Gnomad ASJ exome

AF:

0.00391

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00121

Gnomad NFE exome

AF:

0.00300

Gnomad OTH exome

AF:

0.00415

GnomAD4 exome

AF:

0.00281

AC:

4075

AN:

1451624

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

1978

AN XY:

720566

show subpopulations

Gnomad4 AFR exome

AF:

0.000844

Gnomad4 AMR exome

AF:

0.00378

Gnomad4 ASJ exome

AF:

0.00412

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000244

Gnomad4 FIN exome

AF:

0.000769

Gnomad4 NFE exome

AF:

0.00319

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00242

AC:

368

AN:

152252

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

173

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00530

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00298

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00258

Hom.:

Bravo

AF:

0.00273

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000803

AC:

ESP6500EA

AF:

0.00280

AC:

ExAC

AF:

0.00204

AC:

246

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00405

EpiControl

AF:

0.00451

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CC2D1A: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Intellectual disability, autosomal recessive 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 07, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 08, 2014

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2020

The p.I412V variant (also known as c.1234A>G), located in coding exon 12 of the CC2D1A gene, results from an A to G substitution at nucleotide position 1234. The isoleucine at codon 412 is replaced by valine, an amino acid with highly similar properties. This variant has co-occurred with variants in other intellectual disability (ID)-related genes in individuals from an ID cohort (Grozeva D et al. Hum. Mutat., 2015 Dec;36:1197-204). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CC2D1A-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.0039

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

0.92

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.82

N;.

REVEL

Benign

0.070

Sift

Uncertain

0.018

D;.

Sift4G

Benign

0.093

T;T

Polyphen

0.10

B;B

Vest4

0.15

MVP

0.34

MPC

0.31

ClinPred

0.031

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.098

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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