rs34326474

chr12-41016821-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.2324G>A(p.Ser775Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00171 in 1,614,034 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S775I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0091 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (25 hom.)
• Consequence: CNTN1 NM_001843.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.15

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=0.0043031573).
• BP6: Variant 12-41016821-G-A is Benign according to our data. Variant chr12-41016821-G-A is described in ClinVar as [Benign]. Clinvar id is 128794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00911 (1387/152186) while in subpopulation AFR AF= 0.0311 (1289/41508). AF 95% confidence interval is 0.0296. There are 23 homozygotes in gnomad4. There are 628 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTN1	NM_001843.4	c.2324G>A	p.Ser775Asn	missense_variant	19/24	ENST00000551295.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTN1	ENST00000551295.7	c.2324G>A	p.Ser775Asn	missense_variant	19/24	1	NM_001843.4	P3
CNTN1	ENST00000347616.5	c.2324G>A	p.Ser775Asn	missense_variant	18/23	1		P3
CNTN1	ENST00000348761.2	c.2291G>A	p.Ser764Asn	missense_variant	17/22	1		A1
CNTN1	ENST00000550305.1	n.283G>A		non_coding_transcript_exon_variant	3/6	3

Frequencies

GnomAD3 genomes AF: 0.00909 AC: 1383 AN: 152068 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00247 AC: 620 AN: 251398 Hom.: 9 AF XY: 0.00178 AC XY: 242 AN XY: 135864

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000938 AC: 1371 AN: 1461848 Hom.: 25 Cov.: 32 AF XY: 0.000815 AC XY: 593 AN XY: 727224

Gnomad4 AFR exome AF: 0.0331

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152186 Hom.: 23 Cov.: 32 AF XY: 0.00844 AC XY: 628 AN XY: 74406

Gnomad4 AFR AF: 0.0311

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00232 Hom.: 10

Bravo AF: 0.0102

ESP6500AA AF: 0.0338 AC: 149

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00311 AC: 378

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 29, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Compton-North congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	21
Dann	Benign	0.84
DEOGEN2	Benign	0.30	T;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.93	N;N;N
REVEL	Benign	0.087
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.076	B;B;B
Vest4		0.14
MVP		0.35
MPC		0.32
ClinPred		0.0084	T
GERP RS		2.2
Varity_R		0.082
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs34326474; hg19: chr12-41410623; COSMIC: COSV99049753;