rs148239965

chr12-41027931-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001843.4(CNTN1):c.2785G>A(p.Val929Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,608 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V929V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00082 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (63 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035569966).
• BP6: Variant 12-41027931-G-A is Benign according to our data. Variant chr12-41027931-G-A is described in ClinVar as [Benign]. Clinvar id is 258197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000821 (125/152248) while in subpopulation SAS AF= 0.0243 (117/4820). AF 95% confidence interval is 0.0207. There are 1 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN1	NM_001843.4	c.2785G>A	p.Val929Ile	missense_variant	22/24	ENST00000551295.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN1	ENST00000551295.7	c.2785G>A	p.Val929Ile	missense_variant	22/24	1	NM_001843.4	P3
CNTN1	ENST00000347616.5	c.2785G>A	p.Val929Ile	missense_variant	21/23	1		P3
CNTN1	ENST00000348761.2	c.2752G>A	p.Val918Ile	missense_variant	20/22	1		A1
CNTN1	ENST00000550305.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00316 AC: 795 AN: 251366 Hom.: 19 AF XY: 0.00424 AC XY: 576 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00147 AC: 2151 AN: 1460360 Hom.: 63 Cov.: 30 AF XY: 0.00215 AC XY: 1565 AN XY: 726634

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74438

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0243

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000989 Hom.: 0

Bravo AF: 0.000117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00348 AC: 423

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 03, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2020

- -

Compton-North congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.39	N
MetaRNN	Benign	0.0036	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.70	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.081	B;B;B
Vest4		0.15
MVP		0.17
MPC		0.25
ClinPred		0.014	T
GERP RS		4.6
Varity_R		0.066
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs148239965; hg19: chr12-41421733;