rs9648691

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_014141.6(CNTNAP2):c.3723G>A(p.Ala1241Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,600,224 control chromosomes in the GnomAD database, including 258,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25657 hom., cov: 32)

Exomes 𝑓: 0.56 ( 232974 hom. )

Consequence

CNTNAP2
NM_014141.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.254

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:

LOC105375554 (HGNC:):

LOC105375554 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 7-148409398-G-A is Benign according to our data. Variant chr7-148409398-G-A is described in ClinVar as [Benign]. Clinvar id is 95573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148409398-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.254 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 link	c.3723G>A	p.Ala1241Ala	synonymous_variant	Exon 23 of 24	ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4
LOC105375554	XR_928094.2 link	n.210-14706C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 link	c.3723G>A	p.Ala1241Ala	synonymous_variant	Exon 23 of 24	1	NM_014141.6	ENSP00000354778.3		Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.575

AC:

86956

AN:

151342

Hom.:

25639

Cov.:

show subpopulations

Gnomad AFR

AF:

0.660

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.393

Gnomad ASJ

AF:

0.467

Gnomad EAS

AF:

0.377

Gnomad SAS

AF:

0.620

Gnomad FIN

AF:

0.657

Gnomad MID

AF:

0.417

Gnomad NFE

AF:

0.572

Gnomad OTH

AF:

0.538

GnomAD3 exomes

AF:

0.502

AC:

96596

AN:

192418

Hom.:

31165

AF XY:

0.512

AC XY:

53432

AN XY:

104414

show subpopulations

Gnomad AFR exome

AF:

0.664

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.439

Gnomad EAS exome

AF:

0.305

Gnomad SAS exome

AF:

0.611

Gnomad FIN exome

AF:

0.645

Gnomad NFE exome

AF:

0.544

Gnomad OTH exome

AF:

0.503

GnomAD4 exome

AF:

0.561

AC:

813127

AN:

1448762

Hom.:

232974

Cov.:

AF XY:

0.563

AC XY:

405975

AN XY:

721336

show subpopulations

Gnomad4 AFR exome

AF:

0.664

Gnomad4 AMR exome

AF:

0.312

Gnomad4 ASJ exome

AF:

0.467

Gnomad4 EAS exome

AF:

0.356

Gnomad4 SAS exome

AF:

0.617

Gnomad4 FIN exome

AF:

0.653

Gnomad4 NFE exome

AF:

0.570

Gnomad4 OTH exome

AF:

0.552

GnomAD4 genome

AF:

0.574

AC:

87008

AN:

151462

Hom.:

25657

Cov.:

AF XY:

0.571

AC XY:

42277

AN XY:

74028

show subpopulations

Gnomad4 AFR

AF:

0.659

Gnomad4 AMR

AF:

0.393

Gnomad4 ASJ

AF:

0.467

Gnomad4 EAS

AF:

0.375

Gnomad4 SAS

AF:

0.619

Gnomad4 FIN

AF:

0.657

Gnomad4 NFE

AF:

0.572

Gnomad4 OTH

AF:

0.538

Alfa

AF:

0.543

Hom.:

30663

Bravo

AF:

0.550

Asia WGS

AF:

0.516

AC:

1795

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 17, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Cortical dysplasia-focal epilepsy syndrome

Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pitt-Hopkins-like syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-0.38

CADD

Benign

4.6

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