rs16892095

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378615.1(CC2D2A):c.1127A>C(p.Glu376Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,612,224 control chromosomes in the GnomAD database, including 4,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 489 hom., cov: 32)

Exomes 𝑓: 0.030 ( 3615 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.45

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024175048).

BP6

Variant 4-15516734-A-C is Benign according to our data. Variant chr4-15516734-A-C is described in ClinVar as [Benign]. Clinvar id is 126227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-15516734-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 linkuse as main transcript	c.1127A>C	p.Glu376Ala	missense_variant	11/37	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.1127A>C	p.Glu376Ala	missense_variant	11/37	5	NM_001378615.1	ENSP00000403465	P1	Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

7170

AN:

152114

Hom.:

492

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0396

Gnomad AMI

AF:

0.0297

Gnomad AMR

AF:

0.162

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.249

Gnomad SAS

AF:

0.0990

Gnomad FIN

AF:

0.0379

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00945

Gnomad OTH

AF:

0.0502

GnomAD3 exomes

AF:

0.0764

AC:

18884

AN:

247244

Hom.:

1990

AF XY:

0.0690

AC XY:

9245

AN XY:

134078

show subpopulations

Gnomad AFR exome

AF:

0.0378

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.0274

Gnomad EAS exome

AF:

0.245

Gnomad SAS exome

AF:

0.0892

Gnomad FIN exome

AF:

0.0357

Gnomad NFE exome

AF:

0.00958

Gnomad OTH exome

AF:

0.0598

GnomAD4 exome

AF:

0.0303

AC:

44300

AN:

1459992

Hom.:

3615

Cov.:

AF XY:

0.0308

AC XY:

22369

AN XY:

726162

show subpopulations

Gnomad4 AFR exome

AF:

0.0392

Gnomad4 AMR exome

AF:

0.246

Gnomad4 ASJ exome

AF:

0.0259

Gnomad4 EAS exome

AF:

0.265

Gnomad4 SAS exome

AF:

0.0868

Gnomad4 FIN exome

AF:

0.0327

Gnomad4 NFE exome

AF:

0.00815

Gnomad4 OTH exome

AF:

0.0398

GnomAD4 genome

AF:

0.0471

AC:

7170

AN:

152232

Hom.:

489

Cov.:

AF XY:

0.0526

AC XY:

3916

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0396

Gnomad4 AMR

AF:

0.162

Gnomad4 ASJ

AF:

0.0294

Gnomad4 EAS

AF:

0.249

Gnomad4 SAS

AF:

0.0983

Gnomad4 FIN

AF:

0.0379

Gnomad4 NFE

AF:

0.00947

Gnomad4 OTH

AF:

0.0511

Alfa

AF:

0.0239

Hom.:

531

Bravo

AF:

0.0565

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.0403

AC:

153

ESP6500EA

AF:

0.0102

AC:

ExAC

AF:

0.0666

AC:

8050

Asia WGS

AF:

0.159

AC:

552

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30558011) -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.8

DANN

Benign

0.17

DEOGEN2

Benign

0.063

T;T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.80

T;T;.

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

L;.;L

MutationTaster

Benign

0.82

P;P;P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.32

N;N;N

REVEL

Benign

0.069

Sift

Benign

0.60

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.015

B;.;B

Vest4

0.043

MPC

0.045

ClinPred

0.0026

GERP RS

1.5

Varity_R

0.045

gMVP

0.30

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