rs1861050

Variant names:

• chr4-15480736-C-T
• rs1861050
• ENST00000503658.2:c.262C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_020785.2(CC2D2A):​c.262C>T​(p.Arg88*) 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 NM_020785.2 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -5.90

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]

ACMG classification

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 rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.156C>T	p.Ser52Ser	synonymous_variant	Exon 4 of 37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.156C>T	p.Ser52Ser	synonymous_variant	Exon 4 of 37	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes AF: 0.0788 AC: 11963 AN: 151892 Hom.: 709 Cov.: 32

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

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.: 29 AF XY: 0.0496 AC XY: 35990 AN XY: 725578

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.: 32 AF XY: 0.0828 AC XY: 6156 AN XY: 74304

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 1 Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 6 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.85	T
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	N
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

Other links and lift over

dbSNP: rs1861050; hg19: chr4-15482360; COSMIC: COSV67503288;