12-40908475-A-G

Variant names:

• chr12-40908475-A-G
• rs1944915906
• NM_001843.4:c.43A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001843.4(CNTN1):​c.43A>G​(p.Ile15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,457,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.476
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Compton-North congenital myopathy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067177474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.43A>G	p.Ile15Val	missense_variant	Exon 2 of 24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.43A>G	p.Ile15Val	missense_variant	Exon 2 of 24	1	NM_001843.4	ENSP00000447006.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1457794 Hom.: 0 Cov.: 28 AF XY: 0.00000827 AC XY: 6 AN XY: 725486

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1109010

Other (OTH) AF: 0.00 AC: 0 AN: 60236

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000374 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Compton-North congenital myopathy Uncertain:1

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with CNTN1-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 1027237). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 15 of the CNTN1 protein (p.Ile15Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.8
DANN	Benign	0.29
DEOGEN2	Benign	0.31	.;.;T;T;T;.;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.66	.;T;.;T;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.067	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;.;.;N;.;N;N
PhyloP100		0.48
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.23	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.027
Sift	Benign	0.54	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;B;.;B;B
Vest4		0.064
MVP		0.15
MPC		0.25
ClinPred		0.060	T
GERP RS		2.7
PromoterAI		0.0075	Neutral
Varity_R		0.024
gMVP		0.65
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1944915906; hg19: chr12-41302277; COSMIC: COSV107424814;