rs200796487

chr12-41070009-G-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.3031G>A(p.Gly1011Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000145 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.43

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=0.08469844).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000592 (9/152044) while in subpopulation SAS AF= 0.000207 (1/4822). AF 95% confidence interval is 0.0000477. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. 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.3031G>A	p.Gly1011Ser	missense_variant	24/24	ENST00000551295.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN1	ENST00000551295.7	c.3031G>A	p.Gly1011Ser	missense_variant	24/24	1	NM_001843.4	P3
CNTN1	ENST00000347616.5	c.3031G>A	p.Gly1011Ser	missense_variant	23/23	1		P3
CNTN1	ENST00000348761.2	c.2998G>A	p.Gly1000Ser	missense_variant	22/22	1		A1
CNTN1	ENST00000548481.1	c.*106G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251354 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 101 AN XY: 727198

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: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74248

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Compton-North congenital myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

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: 451957). This variant has not been reported in the literature in individuals affected with CNTN1-related conditions. This variant is present in population databases (rs200796487, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1011 of the CNTN1 protein (p.Gly1011Ser). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2017

A variant of uncertain significance has been identified in the CNTN1 gene. The c.3031 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3031 G>A variant is observed in 4/16510 (0.2%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.3031 G>A creates a cryptic acceptor site which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.3031 G>A variant does not impact splicing, it will result in a G1011S missense variant. The G1011S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Serine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	0.0050
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.060	N;N;.
MutationTaster	Benign	0.78	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.070	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.044	B;B;B
Vest4		0.22
MVP		0.36
MPC		0.89
ClinPred		0.079	T
GERP RS		5.6
Varity_R		0.077
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200796487; hg19: chr12-41463811;