rs387907058

Positions:

chr4-15596110-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378615.1(CC2D2A):c.4340A>C(p.Glu1447Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000213 in 1,548,278 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 6.46

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 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=0.19992965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CC2D2A	NM_001378615.1 linkuse as main transcript	c.4340A>C	p.Glu1447Ala	missense_variant	34/37	ENST00000424120.6
CC2D2A	NM_001080522.2 linkuse as main transcript	c.4340A>C	p.Glu1447Ala	missense_variant	35/38
CC2D2A	NM_001378617.1 linkuse as main transcript	c.4193A>C	p.Glu1398Ala	missense_variant	32/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.4340A>C	p.Glu1447Ala	missense_variant	34/37	5	NM_001378615.1	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000259

AC:

AN:

154312

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

81520

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000664

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1396054

Hom.:

Cov.:

AF XY:

0.0000203

AC XY:

AN XY:

688460

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000260

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with neurodevelopmental disorders to our knowledge; This variant is associated with the following publications: (PMID: 31964843) -

Joubert syndrome 9/15, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2012

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1447 of the CC2D2A protein (p.Glu1447Ala). This variant is present in population databases (rs387907058, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 30934). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CC2D2A-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2023

The CC2D2A c.4340A>C variant is predicted to result in the amino acid substitution p.Glu1447Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0066% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-15597733-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.069

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.74

T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.29

N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.14

Sift

Benign

0.075

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.0

B;B

Vest4

0.21

MutPred

0.53

Loss of solvent accessibility (P = 0.0053);Loss of solvent accessibility (P = 0.0053);

MVP

0.76

MPC

0.045

ClinPred

0.24

GERP RS

5.7

Varity_R

0.23

gMVP

0.59

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