rs759726075

Positions:

• chr4-15579975-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001378615.1(CC2D2A):​c.3779C>T​(p.Ser1260Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S1260S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39293268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CC2D2A	NM_001378615.1	c.3779C>T	p.Ser1260Phe	missense_variant	30/37	ENST00000424120.6
CC2D2A	NM_001080522.2	c.3779C>T	p.Ser1260Phe	missense_variant	31/38
CC2D2A	NM_001378617.1	c.3632C>T	p.Ser1211Phe	missense_variant	28/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CC2D2A	ENST00000424120.6	c.3779C>T	p.Ser1260Phe	missense_variant	30/37	5	NM_001378615.1	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248886 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135024

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2021

This sequence change replaces serine with phenylalanine at codon 1260 of the CC2D2A protein (p.Ser1260Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs759726075, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with CC2D2A-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	0.59	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.10	T;T
Sift4G	Uncertain	0.048	D;D
Polyphen		0.99	D;D
Vest4		0.42
MutPred		0.28		Gain of glycosylation at S1260 (P = 0.0093);Gain of glycosylation at S1260 (P = 0.0093);
MVP		0.91
MPC		0.25
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.80

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: rs759726075; hg19: chr4-15581598;