rs61740537

Positions:

chr4-15557491-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001378615.1(CC2D2A):c.2813T>C(p.Met938Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,605,300 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 0.633

Variant links:

Genes affected

CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

CC2D2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0059105456).

BP6

Variant 4-15557491-T-C is Benign according to our data. Variant chr4-15557491-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281114.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=2}. Variant chr4-15557491-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 linkuse as main transcript	c.2813T>C	p.Met938Thr	missense_variant	21/37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.2813T>C	p.Met938Thr	missense_variant	21/37	5	NM_001378615.1	ENSP00000403465	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00379

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000339

AC:

AN:

232912

Hom.:

AF XY:

0.000269

AC XY:

AN XY:

126408

show subpopulations

Gnomad AFR exome

AF:

0.00361

Gnomad AMR exome

AF:

0.000335

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.000350

GnomAD4 exome

AF:

0.000195

AC:

284

AN:

1452970

Hom.:

Cov.:

AF XY:

0.000192

AC XY:

139

AN XY:

722174

show subpopulations

Gnomad4 AFR exome

AF:

0.00430

Gnomad4 AMR exome

AF:

0.000253

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000470

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000740

Gnomad4 OTH exome

AF:

0.000550

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152330

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00382

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000605

Hom.:

Bravo

AF:

0.00123

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00358

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000398

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CC2D2A: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 28, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 21, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 02, 2016

- -

CC2D2A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 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

0.079

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

7.1

DANN

Benign

0.61

DEOGEN2

Benign

0.061

T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.59

T;.

M_CAP

Benign

0.0092

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.13

N;N

MutationTaster

Benign

0.97

N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.18

MVP

0.69

MPC

0.047

ClinPred

0.0034

GERP RS

2.4

Varity_R

0.028

gMVP

0.19

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