12-40908452-T-A

Variant summary

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

The NM_001843.4(CNTN1):c.20T>A(p.Val7Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. V7V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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=0.28591394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN1	NM_001843.4	c.20T>A	p.Val7Asp	missense_variant	2/24	ENST00000551295.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN1	ENST00000551295.7	c.20T>A	p.Val7Asp	missense_variant	2/24	1	NM_001843.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250820 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135610

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460694 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Invitae

May 03, 2022

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 7 of the CNTN1 protein (p.Val7Asp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CNTN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CNTN1 protein function. 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	0.45
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Benign	0.97
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.76	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N;.;N;.;.;N;.;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;D;N;N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.013	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.21	T;D;T;D;D;T;D;T;T
Polyphen		0.43	B;.;B;.;.;B;.;B;B
Vest4		0.41
MutPred		0.56		Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);
MVP		0.64
MPC		0.52
ClinPred		0.24	T
GERP RS		4.9
Varity_R		0.27
gMVP		0.87

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: rs1236575142; hg19: chr12-41302254;