rs201778720

Positions:

• chr12-41070015-C-A
• chr12-41070015-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001843.4(CNTN1):​c.3037C>A​(p.Leu1013Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1013F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.122

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10252234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN1	NM_001843.4	c.3037C>A	p.Leu1013Ile	missense_variant	24/24	ENST00000551295.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN1	ENST00000551295.7	c.3037C>A	p.Leu1013Ile	missense_variant	24/24	1	NM_001843.4	P3
CNTN1	ENST00000347616.5	c.3037C>A	p.Leu1013Ile	missense_variant	23/23	1		P3
CNTN1	ENST00000348761.2	c.3004C>A	p.Leu1002Ile	missense_variant	22/22	1		A1
CNTN1	ENST00000548481.1	c.*112C>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251324 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135838

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

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: 0.000150

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.3037C>A (p.L1013I) alteration is located in exon 24 (coding exon 23) of the CNTN1 gene. This alteration results from a C to A substitution at nucleotide position 3037, causing the leucine (L) at amino acid position 1013 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Compton-North congenital myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1013 of the CNTN1 protein (p.Leu1013Ile). This variant is present in population databases (rs201778720, gnomAD 0.004%). 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: 2245608). 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 with a negative predictive value of 95%. 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	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.63	N;N;.
MutationTaster	Benign	0.89	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.39	N;N;N
REVEL	Benign	0.012
Sift	Benign	0.061	T;T;D
Sift4G	Benign	0.084	T;T;T
Polyphen		0.023	B;B;B
Vest4		0.13
MutPred		0.42		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.18
MPC		0.55
ClinPred		0.049	T
GERP RS		1.5
Varity_R		0.045
gMVP		0.64

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: rs201778720; hg19: chr12-41463817;