rs1861050

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The ENST00000503658.2(CC2D2A):c.262C>T(p.Arg88Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0532 in 1,610,996 control chromosomes in the GnomAD database, including 4,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.079 ( 705 hom., cov: 32)

Exomes 𝑓: 0.051 ( 3535 hom. )

Consequence

CC2D2A
ENST00000503658.2 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -5.90

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 Benign. Variant got -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 4-15480736-C-T is Benign according to our data. Variant chr4-15480736-C-T is described in ClinVar as [Benign]. Clinvar id is 126229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15480736-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1 linkuse as main transcript	c.156C>T	p.Ser52=	synonymous_variant	4/37	ENST00000424120.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6 linkuse as main transcript	c.156C>T	p.Ser52=	synonymous_variant	4/37	5	NM_001378615.1	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0788

AC:

11963

AN:

151892

Hom.:

709

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.159

Gnomad SAS

AF:

0.0772

Gnomad FIN

AF:

0.0657

Gnomad MID

AF:

0.0224

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0811

GnomAD3 exomes

AF:

0.0865

AC:

20893

AN:

241642

Hom.:

1716

AF XY:

0.0774

AC XY:

10174

AN XY:

131374

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.00857

Gnomad EAS exome

AF:

0.153

Gnomad SAS exome

AF:

0.0685

Gnomad FIN exome

AF:

0.0553

Gnomad NFE exome

AF:

0.0366

Gnomad OTH exome

AF:

0.0708

GnomAD4 exome

AF:

0.0505

AC:

73740

AN:

1458984

Hom.:

3535

Cov.:

AF XY:

0.0496

AC XY:

35990

AN XY:

725578

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.256

Gnomad4 ASJ exome

AF:

0.00917

Gnomad4 EAS exome

AF:

0.164

Gnomad4 SAS exome

AF:

0.0674

Gnomad4 FIN exome

AF:

0.0557

Gnomad4 NFE exome

AF:

0.0358

Gnomad4 OTH exome

AF:

0.0543

GnomAD4 genome

AF:

0.0786

AC:

11954

AN:

152012

Hom.:

705

Cov.:

AF XY:

0.0828

AC XY:

6156

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.186

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.158

Gnomad4 SAS

AF:

0.0763

Gnomad4 FIN

AF:

0.0657

Gnomad4 NFE

AF:

0.0364

Gnomad4 OTH

AF:

0.0817

Alfa

AF:

0.0469

Hom.:

592

Bravo

AF:

0.0904

TwinsUK

AF:

0.0369

AC:

137

ALSPAC

AF:

0.0355

AC:

137

ESP6500AA

AF:

0.0980

AC:

371

ESP6500EA

AF:

0.0376

AC:

310

ExAC

AF:

0.0781

AC:

9436

Asia WGS

AF:

0.124

AC:

432

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 23352160, 27535653) -

Joubert syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Meckel syndrome, type 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Joubert syndrome 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.16

Dann

Benign

0.80

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0011

MutationTaster

Benign

0.0000010

P;P;P;P;P;P;P;P;P

Vest4

0.43

GERP RS

-9.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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