rs2229930

Positions:

• chr12-40981060-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001843.4(CNTN1):​c.1956A>G​(p.Ala652=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 1,612,264 control chromosomes in the GnomAD database, including 1,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (110 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1501 hom.)
• Consequence: CNTN1 NM_001843.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.71

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-40981060-A-G is Benign according to our data. Variant chr12-40981060-A-G is described in ClinVar as [Benign]. Clinvar id is 128793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-40981060-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.71 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.1956A>G	p.Ala652=	synonymous_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.1956A>G	p.Ala652=	synonymous_variant	16/24	1	NM_001843.4	ENSP00000447006	P3
CNTN1	ENST00000347616.5	c.1956A>G	p.Ala652=	synonymous_variant	15/23	1		ENSP00000325660	P3
CNTN1	ENST00000348761.2	c.1923A>G	p.Ala641=	synonymous_variant	14/22	1		ENSP00000261160	A1

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5055 AN: 152244 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.00846

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00653

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0458

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0399 AC: 10004 AN: 250718 Hom.: 244 AF XY: 0.0415 AC XY: 5629 AN XY: 135480

Gnomad AFR exome AF: 0.00806

Gnomad AMR exome AF: 0.0463

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.00500

Gnomad SAS exome AF: 0.0558

Gnomad FIN exome AF: 0.0214

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0507

GnomAD4 exome AF: 0.0422 AC: 61649 AN: 1459902 Hom.: 1501 Cov.: 31 AF XY: 0.0429 AC XY: 31146 AN XY: 726274

Gnomad4 AFR exome AF: 0.00814

Gnomad4 AMR exome AF: 0.0485

Gnomad4 ASJ exome AF: 0.0501

Gnomad4 EAS exome AF: 0.00542

Gnomad4 SAS exome AF: 0.0561

Gnomad4 FIN exome AF: 0.0208

Gnomad4 NFE exome AF: 0.0440

Gnomad4 OTH exome AF: 0.0399

GnomAD4 genome AF: 0.0332 AC: 5059 AN: 152362 Hom.: 110 Cov.: 32 AF XY: 0.0331 AC XY: 2469 AN XY: 74500

Gnomad4 AFR AF: 0.00849

Gnomad4 AMR AF: 0.0467

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.00655

Gnomad4 SAS AF: 0.0563

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0458

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0420 Hom.: 108

Bravo AF: 0.0340

Asia WGS AF: 0.0290 AC: 102 AN: 3476

EpiCase AF: 0.0457

EpiControl AF: 0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 20, 2013	- -

Compton-North congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.45
DANN	Benign	0.56

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: rs2229930; hg19: chr12-41374862;