rs151126410

chr12-40936890-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_001843.4(CNTN1):c.1095G>T(p.Leu365Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000275 in 1,612,938 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.77

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.374644).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000138 (21/152066) while in subpopulation NFE AF= 0.000279 (19/68010). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN1	NM_001843.4	c.1095G>T	p.Leu365Phe	missense_variant	10/24	ENST00000551295.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN1	ENST00000551295.7	c.1095G>T	p.Leu365Phe	missense_variant	10/24	1	NM_001843.4	P3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152066 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000196 AC: 49 AN: 250494 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000289 AC: 422 AN: 1460872 Hom.: 1 Cov.: 33 AF XY: 0.000281 AC XY: 204 AN XY: 726724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 23, 2017

- -

Compton-North congenital myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 06, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 365 of the CNTN1 protein (p.Leu365Phe). This variant is present in population databases (rs151126410, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CNTN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447109). 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	Benign	0.25
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.52	N;N;N;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.016	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.99	D;D;D;D;D
Vest4		0.51
MutPred		0.71		Gain of methylation at K366 (P = 0.0275);Gain of methylation at K366 (P = 0.0275);Gain of methylation at K366 (P = 0.0275);Gain of methylation at K366 (P = 0.0275);.;
MVP		0.36
MPC		1.0
ClinPred		0.41	T
GERP RS		3.4
Varity_R		0.68
gMVP		0.78

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: rs151126410; hg19: chr12-41330692;