12-40910101-T-C

Position:

• chr12-40910101-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.90T>C​(p.His30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,605,248 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (135 hom.)
• Consequence: CNTN1 NM_001843.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.00

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=-0.5).
• BP6: Variant 12-40910101-T-C is Benign according to our data. Variant chr12-40910101-T-C is described in ClinVar as [Benign]. Clinvar id is 258204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.01 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0068 (1035/152302) while in subpopulation NFE AF= 0.0125 (849/68006). AF 95% confidence interval is 0.0118. There are 14 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.90T>C	p.His30=	synonymous_variant	3/24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.90T>C	p.His30=	synonymous_variant	3/24	1	NM_001843.4	ENSP00000447006	P3

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1035 AN: 152184 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00624 AC: 1565 AN: 250910 Hom.: 12 AF XY: 0.00657 AC XY: 891 AN XY: 135658

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.0115 AC: 16741 AN: 1452946 Hom.: 135 Cov.: 27 AF XY: 0.0112 AC XY: 8127 AN XY: 723418

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.00132

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.00963

GnomAD4 genome AF: 0.00680 AC: 1035 AN: 152302 Hom.: 14 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74478

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00916 Hom.: 3

Bravo AF: 0.00746

Asia WGS AF: 0.00116 AC: 4 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CNTN1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 27, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 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. -

Compton-North congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.9
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61748365; hg19: chr12-41303903;