rs139180845

Positions:

chr7-147128836-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_014141.6(CNTNAP2):c.1083G>A(p.Val361=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00374 in 1,613,786 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 21 hom. )

Consequence

CNTNAP2
NM_014141.6 splice_region, synonymous

Scores

Splicing: ADA: 0.9998

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 3.94

Variant links:

Genes affected

CNTNAP2 (HGNC:13830): (contactin associated protein 2) This gene encodes a member of the neurexin family which functions in the vertebrate nervous system as cell adhesion molecules and receptors. This protein, like other neurexin proteins, contains epidermal growth factor repeats and laminin G domains. In addition, it includes an F5/8 type C domain, discoidin/neuropilin- and fibrinogen-like domains, thrombospondin N-terminal-like domains and a putative PDZ binding site. This protein is localized at the juxtaparanodes of myelinated axons, and mediates interactions between neurons and glia during nervous system development and is also involved in localization of potassium channels within differentiating axons. This gene encompasses almost 1.5% of chromosome 7 and is one of the largest genes in the human genome. It is directly bound and regulated by forkhead box protein P2, a transcription factor related to speech and language development. This gene has been implicated in multiple neurodevelopmental disorders, including Gilles de la Tourette syndrome, schizophrenia, epilepsy, autism, ADHD and intellectual disability. [provided by RefSeq, Jul 2017]

CNTNAP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 7-147128836-G-A is Benign according to our data. Variant chr7-147128836-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95554.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=1}. Variant chr7-147128836-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.1083G>A	p.Val361=	splice_region_variant, synonymous_variant	7/24	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3 linkuse as main transcript	c.1083G>A	p.Val361=	splice_region_variant, synonymous_variant	7/14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 linkuse as main transcript	c.1083G>A	p.Val361=	splice_region_variant, synonymous_variant	7/24	1	NM_014141.6	ENSP00000354778	P1	Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

401

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00597

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00280

AC:

704

AN:

251296

Hom.:

AF XY:

0.00282

AC XY:

383

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.00346

Gnomad NFE exome

AF:

0.00491

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00386

AC:

5636

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

2787

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.00408

Gnomad4 NFE exome

AF:

0.00460

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.00264

AC:

401

AN:

152126

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

201

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000771

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00597

Gnomad4 NFE

AF:

0.00425

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00377

Hom.:

Bravo

AF:

0.00209

Asia WGS

AF:

0.000579

AC:

AN:

3466

EpiCase

AF:

0.00229

EpiControl

AF:

0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2017	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 11, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CNTNAP2: BS2 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CNTNAP2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Benign

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.39

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over