12-40908572-A-C

Variant names:

• chr12-40908572-A-C
• rs35684552
• NM_001843.4:c.61+79A>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.61+79A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,076,696 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (112 hom., cov: 32)
  • Exomes 𝑓: 0.041 (928 hom.)
• Consequence: CNTN1 NM_001843.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0560
• Publications: 2 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=-0.81).
• BP6: Variant 12-40908572-A-C is Benign according to our data. Variant chr12-40908572-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 679918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.61+79A>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.61+79A>C		intron_variant	Intron 2 of 23	1	NM_001843.4	ENSP00000447006.1

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5088 AN: 152206 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.00863

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.0462

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.00634

Gnomad SAS AF: 0.0512

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0407

GnomAD4 exome AF: 0.0411 AC: 38030 AN: 924372 Hom.: 928 AF XY: 0.0420 AC XY: 19964 AN XY: 475114

African (AFR) AF: 0.00857 AC: 183 AN: 21360

American (AMR) AF: 0.0505 AC: 1746 AN: 34556

Ashkenazi Jewish (ASJ) AF: 0.0544 AC: 1141 AN: 20978

East Asian (EAS) AF: 0.00499 AC: 175 AN: 35084

South Asian (SAS) AF: 0.0527 AC: 3511 AN: 66612

European-Finnish (FIN) AF: 0.0214 AC: 906 AN: 42320

Middle Eastern (MID) AF: 0.0834 AC: 252 AN: 3020

European-Non Finnish (NFE) AF: 0.0432 AC: 28465 AN: 658706

Other (OTH) AF: 0.0396 AC: 1651 AN: 41736

GnomAD4 genome AF: 0.0335 AC: 5096 AN: 152324 Hom.: 112 Cov.: 32 AF XY: 0.0336 AC XY: 2500 AN XY: 74476

African (AFR) AF: 0.00866 AC: 360 AN: 41590

American (AMR) AF: 0.0462 AC: 707 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 174 AN: 3472

East Asian (EAS) AF: 0.00635 AC: 33 AN: 5194

South Asian (SAS) AF: 0.0522 AC: 252 AN: 4824

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10614

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0463 AC: 3150 AN: 68024

Other (OTH) AF: 0.0402 AC: 85 AN: 2112

Alfa AF: 0.0399 Hom.: 17

Bravo AF: 0.0341

Asia WGS AF: 0.0270 AC: 92 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Likely 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.9
DANN	Benign	0.58
PhyloP100		0.056
PromoterAI		-0.011	Neutral
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: rs35684552; hg19: chr12-41302374;