12-40908421-A-G

Variant names:

• chr12-40908421-A-G
• rs115378305
• NM_001843.4:c.-12A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001843.4(CNTN1):​c.-12A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,612,220 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (10 hom.)
• Consequence: CNTN1 NM_001843.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.130
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-40908421-A-G is Benign according to our data. Variant chr12-40908421-A-G is described in ClinVar as [Benign]. Clinvar id is 384607.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00784 (1194/152222) while in subpopulation AFR AF = 0.0274 (1137/41540). AF 95% confidence interval is 0.026. There are 17 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTN1	NM_001843.4	c.-12A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 24	ENST00000551295.7	NP_001834.2
CNTN1	NM_001843.4	c.-12A>G		5_prime_UTR_variant	Exon 2 of 24	ENST00000551295.7	NP_001834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTN1	ENST00000551295.7	c.-12A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 24	1	NM_001843.4	ENSP00000447006.1
CNTN1	ENST00000551295.7	c.-12A>G		5_prime_UTR_variant	Exon 2 of 24	1	NM_001843.4	ENSP00000447006.1

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1193 AN: 152104 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00196 AC: 491 AN: 250782 AF XY: 0.00141

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000776 AC: 1133 AN: 1459998 Hom.: 10 Cov.: 29 AF XY: 0.000657 AC XY: 477 AN XY: 726412

African (AFR) AF: 0.0277 AC: 924 AN: 33410

American (AMR) AF: 0.00136 AC: 61 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5750

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1110798

Other (OTH) AF: 0.00138 AC: 83 AN: 60310

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152222 Hom.: 17 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74428

African (AFR) AF: 0.0274 AC: 1137 AN: 41540

American (AMR) AF: 0.00262 AC: 40 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00278 Hom.: 1

Bravo AF: 0.00875

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 08, 2016

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	-0.89
CADD	Benign	2.8
DANN	Benign	0.27
PhyloP100		0.13
PromoterAI		0.0048	Neutral
Mutation Taster		=300/0	polymorphism

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: rs115378305; hg19: chr12-41302223; COSMIC: COSV61643344;