12-40910023-A-C

Variant names:

• chr12-40910023-A-C
• rs2304819
• NM_001843.4:c.62-50A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001843.4(CNTN1):​c.62-50A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,376,668 control chromosomes in the GnomAD database, including 58,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4978 hom., cov: 32)
  • Exomes 𝑓: 0.29 (53375 hom.)
• Consequence: CNTN1 NM_001843.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.645
• Publications: 3 publications found

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]

CNTN1 Gene-Disease associations (from GenCC):

• Compton-North congenital myopathy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-40910023-A-C is Benign according to our data. Variant chr12-40910023-A-C is described in ClinVar as [Benign]. Clinvar id is 680155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.316 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.62-50A>C		intron_variant	Intron 2 of 23	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.62-50A>C		intron_variant	Intron 2 of 23	1	NM_001843.4	ENSP00000447006.1

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36353 AN: 151904 Hom.: 4988 Cov.: 32

Gnomad AFR AF: 0.0993

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.270

GnomAD2 exomes AF: 0.270 AC: 67223 AN: 248762 AF XY: 0.281

Gnomad AFR exome AF: 0.0921

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.224

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.291 AC: 356110 AN: 1224646 Hom.: 53375 Cov.: 17 AF XY: 0.295 AC XY: 183068 AN XY: 621364

African (AFR) AF: 0.0935 AC: 2724 AN: 29134

American (AMR) AF: 0.165 AC: 7288 AN: 44270

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 9060 AN: 24488

East Asian (EAS) AF: 0.203 AC: 7790 AN: 38320

South Asian (SAS) AF: 0.320 AC: 26013 AN: 81286

European-Finnish (FIN) AF: 0.270 AC: 13690 AN: 50782

Middle Eastern (MID) AF: 0.317 AC: 1696 AN: 5348

European-Non Finnish (NFE) AF: 0.303 AC: 272513 AN: 898694

Other (OTH) AF: 0.293 AC: 15336 AN: 52324

GnomAD4 genome AF: 0.239 AC: 36334 AN: 152022 Hom.: 4978 Cov.: 32 AF XY: 0.238 AC XY: 17720 AN XY: 74330

African (AFR) AF: 0.0991 AC: 4116 AN: 41516

American (AMR) AF: 0.224 AC: 3426 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1256 AN: 3464

East Asian (EAS) AF: 0.227 AC: 1177 AN: 5176

South Asian (SAS) AF: 0.330 AC: 1590 AN: 4820

European-Finnish (FIN) AF: 0.261 AC: 2751 AN: 10560

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21115 AN: 67902

Other (OTH) AF: 0.267 AC: 562 AN: 2108

Alfa AF: 0.289 Hom.: 2047

Bravo AF: 0.225

Asia WGS AF: 0.248 AC: 860 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.1
DANN	Benign	0.69
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304819; hg19: chr12-41303825; COSMIC: COSV61636349;