rs186486235

Positions:

chr4-15597428-C-T

Variant summary

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

The NM_001378615.1(CC2D2A):c.4459C>T(p.Arg1487Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,552,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R1487H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.748

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:

CC2D2A (HGNC:):

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=0.0036909282).

BP6

Variant 4-15597428-C-T is Benign according to our data. Variant chr4-15597428-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238281.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 linkuse as main transcript	c.4459C>T	p.Arg1487Cys	missense_variant	35/37	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2 linkuse as main transcript	c.4459C>T	p.Arg1487Cys	missense_variant	36/38		NP_001073991.2	Q9P2K1-4
CC2D2A	NM_001378617.1 linkuse as main transcript	c.4312C>T	p.Arg1438Cys	missense_variant	33/35		NP_001365546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.4459C>T	p.Arg1487Cys	missense_variant	35/37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.00240

AC:

365

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00809

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.0000441

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000453

AC:

AN:

161232

Hom.:

AF XY:

0.000388

AC XY:

AN XY:

85032

show subpopulations

Gnomad AFR exome

AF:

0.00680

Gnomad AMR exome

AF:

0.000524

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000889

Gnomad SAS exome

AF:

0.0000437

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000243

AC:

340

AN:

1400438

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

147

AN XY:

690930

show subpopulations

Gnomad4 AFR exome

AF:

0.00837

Gnomad4 AMR exome

AF:

0.000614

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000278

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000927

Gnomad4 OTH exome

AF:

0.000655

GnomAD4 genome

AF:

0.00240

AC:

365

AN:

152226

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00806

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000478

Hom.:

Bravo

AF:

0.00253

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00575

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000392

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Meckel syndrome, type 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Joubert syndrome 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.83

T;.

M_CAP

Benign

0.029

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.082

Sift

Benign

0.077

T;T

Sift4G

Benign

0.082

T;T

Polyphen

0.021

B;B

Vest4

0.13

MVP

0.63

MPC

0.054

ClinPred

0.029

GERP RS

2.7

Varity_R

0.075

gMVP

0.48

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