rs151126410

Positions:

chr12-40936890-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.77

Variant links:

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]

CNTN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CNTN1	NM_001843.4 linkuse as main transcript	c.1095G>T	p.Leu365Phe	missense_variant	10/24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7 linkuse as main transcript	c.1095G>T	p.Leu365Phe	missense_variant	10/24	1	NM_001843.4	ENSP00000447006	P3	Q12860-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

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:

AN:

250494

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135344

show subpopulations

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.:

Cov.:

AF XY:

0.000281

AC XY:

204

AN XY:

726724

show subpopulations

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:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000943

AC XY:

AN XY:

74266

show subpopulations

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.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

.;D;.;D;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;.;D;D;D

M_CAP

Benign

0.048

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.52

N;N;N;N;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.66

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over