rs62000428

chr4-15514710-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378615.1(CC2D2A):c.721G>A(p.Glu241Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,530,718 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (10 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 8.05

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]

LOC124900672 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004833162).
• BP6: Variant 4-15514710-G-A is Benign according to our data. Variant chr4-15514710-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 126247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00686 (1045/152298) while in subpopulation AFR AF= 0.0236 (981/41548). AF 95% confidence interval is 0.0224. There are 16 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.721G>A	p.Glu241Lys	missense_variant	9/37	ENST00000424120.6
LOC124900672	XR_007058062.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.721G>A	p.Glu241Lys	missense_variant	9/37	5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 1038 AN: 152180 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00197 AC: 434 AN: 220178 Hom.: 6 AF XY: 0.00144 AC XY: 173 AN XY: 119858

Gnomad AFR exome AF: 0.0248

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.000351

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000771 AC: 1063 AN: 1378420 Hom.: 10 Cov.: 30 AF XY: 0.000687 AC XY: 466 AN XY: 678214

Gnomad4 AFR exome AF: 0.0247

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.000380

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000753

Gnomad4 OTH exome AF: 0.00186

GnomAD4 genome AF: 0.00686 AC: 1045 AN: 152298 Hom.: 16 Cov.: 33 AF XY: 0.00658 AC XY: 490 AN XY: 74478

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00153 Hom.: 7

Bravo AF: 0.00808

ESP6500AA AF: 0.0220 AC: 84

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00229 AC: 277

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 24, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Meckel syndrome, type 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Joubert syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;.
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.14	T;D;T
Sift4G	Uncertain	0.018	D;T;D
Polyphen		0.70	P;.;P
Vest4		0.50
MVP		0.41
MPC		0.073
ClinPred		0.023	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.52

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

Other links and lift over

dbSNP: rs62000428; hg19: chr4-15516333; COSMIC: COSV99067342; COSMIC: COSV99067342;