rs144439937

chr4-15533245-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378615.1(CC2D2A):c.1519A>G(p.Lys507Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0085 in 1,602,406 control chromosomes in the GnomAD database, including 71 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 0.0063 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (65 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 6.43

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011331022).
• BP6: Variant 4-15533245-A-G is Benign according to our data. Variant chr4-15533245-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126228.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=1, Uncertain_significance=2}. Variant chr4-15533245-A-G is described in Lovd as [Benign]. Variant chr4-15533245-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00632 (963/152352) while in subpopulation NFE AF= 0.0098 (667/68028). AF 95% confidence interval is 0.00919. There are 6 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.1519A>G	p.Lys507Glu	missense_variant	14/37	ENST00000424120.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.1519A>G	p.Lys507Glu	missense_variant	14/37	5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 962 AN: 152234 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00980

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00644 AC: 1528 AN: 237250 Hom.: 4 AF XY: 0.00648 AC XY: 834 AN XY: 128642

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00201

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00606

GnomAD4 exome AF: 0.00873 AC: 12659 AN: 1450054 Hom.: 65 Cov.: 30 AF XY: 0.00855 AC XY: 6162 AN XY: 720786

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.00417

Gnomad4 ASJ exome AF: 0.00274

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.00563

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.00632 AC: 963 AN: 152352 Hom.: 6 Cov.: 33 AF XY: 0.00600 AC XY: 447 AN XY: 74506

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.00980

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00879 Hom.: 12

Bravo AF: 0.00585

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00166 AC: 6

ESP6500EA AF: 0.0101 AC: 82

ExAC AF: 0.00659 AC: 796

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Jan 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2017	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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CC2D2A: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 30, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Meckel syndrome, type 6 Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Joubert syndrome 9 Uncertain:1

Uncertain significance, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;.
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N;D;N
REVEL	Pathogenic	0.68
Sift	Benign	0.042	D;D;D
Sift4G	Uncertain	0.0050	D;T;D
Polyphen		1.0	D;.;D
Vest4		0.61
MVP		0.91
MPC		0.26
ClinPred		0.010	T
GERP RS		5.2
Varity_R		0.40
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: rs144439937; hg19: chr4-15534868;