rs371086728

Positions:

• chr4-15516648-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_001378615.1(CC2D2A):​c.1041C>T​(p.Asp347Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,612,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: CC2D2A NM_001378615.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: -0.369

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 4-15516648-C-T is Benign according to our data. Variant chr4-15516648-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166802.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=1}. Variant chr4-15516648-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.369 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.1041C>T	p.Asp347Asp	synonymous_variant	11/37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.1041C>T	p.Asp347Asp	synonymous_variant	11/37	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000894 AC: 222 AN: 248248 Hom.: 0 AF XY: 0.00114 AC XY: 153 AN XY: 134690

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.000335

Gnomad SAS exome AF: 0.00306

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000808

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000670 AC: 978 AN: 1460404 Hom.: 1 Cov.: 30 AF XY: 0.000776 AC XY: 564 AN XY: 726452

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00294

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000560

Gnomad4 OTH exome AF: 0.000879

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74438

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000899 Hom.: 0

Bravo AF: 0.000616

EpiCase AF: 0.000820

EpiControl AF: 0.00143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CC2D2A: BP4, BP7 -

Joubert syndrome 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP4. -
Uncertain significance, 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, 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 syndrome, type 6 Uncertain:1

Uncertain significance, 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, 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. -

Retinal dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

CC2D2A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.7
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs371086728; hg19: chr4-15518271; COSMIC: COSV67503482; COSMIC: COSV67503482;