12-41016791-G-A

Position:

• chr12-41016791-G-A

Variant summary

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

The ENST00000551295.7(CNTN1):​c.2294G>A​(p.Gly765Asp) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNTN1 ENST00000551295.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84

Genes affected

CNTN1 (HGNC:2171): (contactin 1) The protein encoded by this gene is a member of the immunoglobulin superfamily. It is a glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein that functions as a cell adhesion molecule. It may play a role in the formation of axon connections in the developing nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

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=0.3390314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.2294G>A	p.Gly765Asp	missense_variant	19/24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.2294G>A	p.Gly765Asp	missense_variant	19/24	1	NM_001843.4	ENSP00000447006	P3
CNTN1	ENST00000347616.5	c.2294G>A	p.Gly765Asp	missense_variant	18/23	1		ENSP00000325660	P3
CNTN1	ENST00000348761.2	c.2261G>A	p.Gly754Asp	missense_variant	17/22	1		ENSP00000261160	A1
CNTN1	ENST00000550305.1	n.253G>A		non_coding_transcript_exon_variant	3/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Compton-North congenital myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2016

This sequence change replaces glycine with aspartic acid at codon 765 of the CNTN1 protein (p.Gly765Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CNTN1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.98	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.084	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.94	P;P;P
Vest4		0.17
MutPred		0.32		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.43
MPC		0.43
ClinPred		0.57	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.75

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: rs1555199605; hg19: chr12-41410593;