rs2286128

Positions:

chr7-147485974-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014141.6(CNTNAP2):c.1710G>A(p.Ser570=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0096 in 1,613,978 control chromosomes in the GnomAD database, including 622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 237 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 385 hom. )

Consequence

CNTNAP2
NM_014141.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.42

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 7-147485974-G-A is Benign according to our data. Variant chr7-147485974-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-147485974-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.41 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.1710G>A	p.Ser570=	synonymous_variant	11/24	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3 linkuse as main transcript	c.1710G>A	p.Ser570=	synonymous_variant	11/14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 linkuse as main transcript	c.1710G>A	p.Ser570=	synonymous_variant	11/24	1	NM_014141.6	ENSP00000354778	P1	Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.0345

AC:

5237

AN:

152012

Hom.:

236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0997

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0503

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0385

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.0316

GnomAD3 exomes

AF:

0.0196

AC:

4921

AN:

251470

Hom.:

191

AF XY:

0.0145

AC XY:

1976

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0737

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0262

Gnomad SAS exome

AF:

0.00330

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.00700

AC:

10236

AN:

1461848

Hom.:

385

Cov.:

AF XY:

0.00619

AC XY:

4505

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0963

Gnomad4 AMR exome

AF:

0.0730

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0571

Gnomad4 SAS exome

AF:

0.00339

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000374

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.0345

AC:

5252

AN:

152130

Hom.:

237

Cov.:

AF XY:

0.0341

AC XY:

2535

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0997

Gnomad4 AMR

AF:

0.0502

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.0386

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.0318

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0421

Asia WGS

AF:

0.0280

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 10, 2013	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Cortical dysplasia-focal epilepsy syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Pitt-Hopkins-like syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.8

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

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