12-41020410-T-C

Position:

• chr12-41020410-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001843.4(CNTN1):​c.2493T>C​(p.His831=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,611,820 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (80 hom.)
• Consequence: CNTN1 NM_001843.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0150

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=-0.52).
• BP6: Variant 12-41020410-T-C is Benign according to our data. Variant chr12-41020410-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.015 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00443 (675/152296) while in subpopulation SAS AF= 0.0159 (77/4830). AF 95% confidence interval is 0.0131. There are 7 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.2493T>C	p.His831=	synonymous_variant	20/24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.2493T>C	p.His831=	synonymous_variant	20/24	1	NM_001843.4	ENSP00000447006	P3
CNTN1	ENST00000347616.5	c.2493T>C	p.His831=	synonymous_variant	19/23	1		ENSP00000325660	P3
CNTN1	ENST00000348761.2	c.2460T>C	p.His820=	synonymous_variant	18/22	1		ENSP00000261160	A1
CNTN1	ENST00000550305.1	n.452T>C		non_coding_transcript_exon_variant	4/6	3

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 676 AN: 152178 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0159

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00440

Gnomad OTH AF: 0.00958

GnomAD3 exomes AF: 0.00714 AC: 1789 AN: 250498 Hom.: 21 AF XY: 0.00823 AC XY: 1115 AN XY: 135442

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.00438

Gnomad ASJ exome AF: 0.0398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0191

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00512

Gnomad OTH exome AF: 0.00918

GnomAD4 exome AF: 0.00488 AC: 7127 AN: 1459524 Hom.: 80 Cov.: 29 AF XY: 0.00556 AC XY: 4040 AN XY: 726120

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.0379

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0193

Gnomad4 FIN exome AF: 0.000525

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00813

GnomAD4 genome AF: 0.00443 AC: 675 AN: 152296 Hom.: 7 Cov.: 33 AF XY: 0.00484 AC XY: 360 AN XY: 74456

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0159

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00440

Gnomad4 OTH AF: 0.00948

Alfa AF: 0.00675 Hom.: 4

Bravo AF: 0.00433

ClinVar

Significance: Benign/Likely 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	Jun 08, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 16, 2013	- -

Compton-North congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely 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	-0.52
CADD	Benign	4.3
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: rs61754102; hg19: chr12-41414212;