rs16892134

chr4-15538112-G-Achr4-15538112-G-Cchr4-15538112-G-T

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.1978G>A(p.Val660Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,595,412 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V660L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (15 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.309

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=0.003638178).
• BP6: Variant 4-15538112-G-A is Benign according to our data. Variant chr4-15538112-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210608.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr4-15538112-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.006 (914/152220) while in subpopulation AFR AF= 0.0208 (862/41536). AF 95% confidence interval is 0.0196. There are 7 homozygotes in gnomad4. There are 431 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.1978G>A	p.Val660Ile	missense_variant	16/37	ENST00000424120.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.1978G>A	p.Val660Ile	missense_variant	16/37	5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes AF: 0.00595 AC: 905 AN: 152102 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00139 AC: 308 AN: 221472 Hom.: 4 AF XY: 0.00104 AC XY: 124 AN XY: 119286

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000830

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000803

Gnomad OTH exome AF: 0.00127

GnomAD4 exome AF: 0.000714 AC: 1030 AN: 1443192 Hom.: 15 Cov.: 33 AF XY: 0.000580 AC XY: 415 AN XY: 715450

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000481

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000535

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00600 AC: 914 AN: 152220 Hom.: 7 Cov.: 32 AF XY: 0.00579 AC XY: 431 AN XY: 74414

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000666 Hom.: 2

Bravo AF: 0.00737

ESP6500AA AF: 0.0212 AC: 93

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00156 AC: 189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 24, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2018

This variant is associated with the following publications: (PMID: 22241855) -

Joubert syndrome 9 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	0.37
Dann	Benign	0.30
DEOGEN2	Benign	0.053	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.61	T;.
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N;N
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.019
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.041	B;B
Vest4		0.044
MVP		0.14
MPC		0.038
ClinPred		0.00064	T
GERP RS		1.5
Varity_R		0.018
gMVP		0.11

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: rs16892134; hg19: chr4-15539735;