rs202057391

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017721.5(CC2D1A):c.1739C>T(p.Thr580Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,614,038 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0054 ( 24 hom. )

Consequence

CC2D1A
NM_017721.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:6

Conservation

PhyloP100: 1.50

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077696443).

BP6

Variant 19-13923430-C-T is Benign according to our data. Variant chr19-13923430-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128618.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Pathogenic=1, Benign=3}. Variant chr19-13923430-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D1A	NM_017721.5 linkuse as main transcript	c.1739C>T	p.Thr580Ile	missense_variant	15/29	ENST00000318003.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D1A	ENST00000318003.11 linkuse as main transcript	c.1739C>T	p.Thr580Ile	missense_variant	15/29	1	NM_017721.5	P3	Q6P1N0-1

Frequencies

GnomAD3 genomes

AF:

0.00463

AC:

705

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00866

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00508

AC:

1264

AN:

249050

Hom.:

AF XY:

0.00537

AC XY:

725

AN XY:

135134

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00510

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00216

Gnomad FIN exome

AF:

0.00961

Gnomad NFE exome

AF:

0.00639

Gnomad OTH exome

AF:

0.00596

GnomAD4 exome

AF:

0.00545

AC:

7965

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00543

AC XY:

3951

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00519

Gnomad4 ASJ exome

AF:

0.00333

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00205

Gnomad4 FIN exome

AF:

0.00905

Gnomad4 NFE exome

AF:

0.00595

Gnomad4 OTH exome

AF:

0.00507

GnomAD4 genome

AF:

0.00463

AC:

706

AN:

152336

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

370

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00866

Gnomad4 NFE

AF:

0.00660

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.00601

Hom.:

Bravo

AF:

0.00437

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00123

AC:

ESP6500EA

AF:

0.00696

AC:

ExAC

AF:

0.00470

AC:

568

EpiCase

AF:

0.00616

EpiControl

AF:

0.00729

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 07, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CC2D1A: BS2 -

Smith-Magenis Syndrome-like

Pathogenic:1

Pathogenic, flagged submission

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Aug 15, 2016

- -

Intellectual disability, autosomal recessive 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

CC2D1A-related condition

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2021

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

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 28, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.090

T;.

Eigen

Benign

-0.035

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.95

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.025

Sift

Benign

0.27

T;.

Sift4G

Benign

0.33

T;T

Polyphen

0.24

B;B

Vest4

0.51

MVP

0.37

MPC

0.29

ClinPred

0.011

GERP RS

5.2

Varity_R

0.060

gMVP

0.23

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