12-40908459-T-A

Position:

• chr12-40908459-T-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001843.4(CNTN1):​c.27T>A​(p.His9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.184

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08900809).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000822 (12/1460424) while in subpopulation EAS AF= 0.000303 (12/39600). AF 95% confidence interval is 0.000175. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 29. 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.27T>A	p.His9Gln	missense_variant	2/24	ENST00000551295.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN1	ENST00000551295.7	c.27T>A	p.His9Gln	missense_variant	2/24	1	NM_001843.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000798 AC: 2 AN: 250726 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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: 0.00000822 AC: 12 AN: 1460424 Hom.: 0 Cov.: 29 AF XY: 0.00000688 AC XY: 5 AN XY: 726582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000303

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

ExAC AF: 0.00000824 AC: 1

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

Dec 06, 2022

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 9 of the CNTN1 protein (p.His9Gln). 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: 1415620). This variant has not been reported in the literature in individuals affected with CNTN1-related conditions. This variant is present in population databases (rs745850349, gnomAD 0.01%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	10
DANN	Benign	0.55
DEOGEN2	Benign	0.30	.;.;T;T;T;.;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.58	.;T;.;T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.089	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;.;.;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.92	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.66	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;B;.;B;B
Vest4		0.22
MutPred		0.53		Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);Gain of catalytic residue at H9 (P = 0.0237);
MVP		0.48
MPC		0.31
ClinPred		0.017	T
GERP RS		-1.1
Varity_R		0.058
gMVP		0.68

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: rs745850349; hg19: chr12-41302261;