rs376443152

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_017721.5(CC2D1A):c.2707C>T(p.Arg903Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,294,950 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R903Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 14)

Exomes 𝑓: 0.00018 ( 3 hom. )

Consequence

CC2D1A
NM_017721.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.921

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
intellectual disability, autosomal recessive 3
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CC2D1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08847353).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D1A	NM_017721.5 link	c.2707C>T	p.Arg903Trp	missense_variant	Exon 26 of 29	ENST00000318003.11	NP_060191.3	Q6P1N0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D1A	ENST00000318003.11 link	c.2707C>T	p.Arg903Trp	missense_variant	Exon 26 of 29	1	NM_017721.5	ENSP00000313601.6		Q6P1N0-1

Frequencies

GnomAD3 genomes

AF:

0.000314

AC:

AN:

79622

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000781

Gnomad ASJ

AF:

0.00135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000973

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000293

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000308

AC:

AN:

126696

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000329

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000203

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.000907

GnomAD4 exome

AF:

0.000177

AC:

215

AN:

1215294

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

115

AN XY:

594620

show subpopulations

African (AFR)

AF:

0.0000367

AC:

AN:

27250

American (AMR)

AF:

0.000203

AC:

AN:

29628

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

19160

East Asian (EAS)

AF:

0.0000425

AC:

AN:

23554

South Asian (SAS)

AF:

0.000599

AC:

AN:

68406

European-Finnish (FIN)

AF:

0.000146

AC:

AN:

34266

Middle Eastern (MID)

AF:

0.00234

AC:

AN:

4698

European-Non Finnish (NFE)

AF:

0.000129

AC:

124

AN:

961692

Other (OTH)

AF:

0.000322

AC:

AN:

46640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000314

AC:

AN:

79656

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

AN XY:

36926

show subpopulations

African (AFR)

AF:

0.000155

AC:

AN:

19344

American (AMR)

AF:

0.000779

AC:

AN:

6420

Ashkenazi Jewish (ASJ)

AF:

0.00135

AC:

AN:

2218

East Asian (EAS)

AF:

0.00

AC:

AN:

2964

South Asian (SAS)

AF:

0.000980

AC:

AN:

2040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

170

European-Non Finnish (NFE)

AF:

0.000293

AC:

AN:

40946

Other (OTH)

AF:

0.00

AC:

AN:

1028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000278

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.000169

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 21, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R903W variant (also known as c.2707C>T), located in coding exon 26 of the CC2D1A gene, results from a C to T substitution at nucleotide position 2707. The arginine at codon 903 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is 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. -

not provided

Uncertain:1

Mar 24, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal recessive 3

Uncertain:1

Jul 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.088

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

PhyloP100

-0.92

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.15

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.012

D;D

Polyphen

1.0

D;D

Vest4

0.48

MVP

0.39

MPC

0.64

ClinPred

0.064

GERP RS

0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.096

gMVP

0.33

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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rs376443152

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over