rs199886411

Positions:

• chr12-40980999-G-A
• chr12-40980999-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The ENST00000551295.7(CNTN1):​c.1895G>A​(p.Ser632Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CNTN1 ENST00000551295.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00000205 (3/1461424) while in subpopulation AFR AF= 0.0000897 (3/33462). AF 95% confidence interval is 0.0000238. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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	c.1895G>A	p.Ser632Asn	missense_variant	16/24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.1895G>A	p.Ser632Asn	missense_variant	16/24	1	NM_001843.4	ENSP00000447006	P3
CNTN1	ENST00000347616.5	c.1895G>A	p.Ser632Asn	missense_variant	15/23	1		ENSP00000325660	P3
CNTN1	ENST00000348761.2	c.1862G>A	p.Ser621Asn	missense_variant	14/22	1		ENSP00000261160	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461424 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727036

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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

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

Nov 21, 2020

This sequence change replaces serine with asparagine at codon 632 of the CNTN1 protein (p.Ser632Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CNTN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 576180). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	2.9	M;M;.
MutationTaster	Benign	0.70	N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.83	P;P;P
Vest4		0.53
MutPred		0.64		Gain of catalytic residue at S632 (P = 0.0613);Gain of catalytic residue at S632 (P = 0.0613);.;
MVP		0.62
MPC		0.39
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.36
gMVP		0.76

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: rs199886411; hg19: chr12-41374801;