rs9648691

Variant names:

• chr7-148409398-G-A
• rs9648691
• NM_014141.6:c.3723G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.254
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR, AD Classification: DEFINITIVE, NO_KNOWN Submitted by: ClinGen
• cortical dysplasia-focal epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ENSG00000287636 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 95573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.3723G>A	p.Ala1241Ala	synonymous_variant	Exon 23 of 24	ENST00000361727.8	NP_054860.1
LOC105375554	XR_928094.2	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	c.3723G>A	p.Ala1241Ala	synonymous_variant	Exon 23 of 24	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.575 AC: 86956 AN: 151342 Hom.: 25639 Cov.: 32

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

GnomAD2 exomes AF: 0.502 AC: 96596 AN: 192418 AF XY: 0.512

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 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.: 34 AF XY: 0.563 AC XY: 405975 AN XY: 721336

African (AFR) AF: 0.664 AC: 22057 AN: 33230

American (AMR) AF: 0.312 AC: 13912 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 12162 AN: 26032

East Asian (EAS) AF: 0.356 AC: 14106 AN: 39618

South Asian (SAS) AF: 0.617 AC: 53024 AN: 85990

European-Finnish (FIN) AF: 0.653 AC: 34799 AN: 53284

Middle Eastern (MID) AF: 0.476 AC: 2728 AN: 5734

European-Non Finnish (NFE) AF: 0.570 AC: 627290 AN: 1100312

Other (OTH) AF: 0.552 AC: 33049 AN: 59910

GnomAD4 genome AF: 0.574 AC: 87008 AN: 151462 Hom.: 25657 Cov.: 32 AF XY: 0.571 AC XY: 42277 AN XY: 74028

African (AFR) AF: 0.659 AC: 27223 AN: 41296

American (AMR) AF: 0.393 AC: 5989 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1615 AN: 3458

East Asian (EAS) AF: 0.375 AC: 1933 AN: 5148

South Asian (SAS) AF: 0.619 AC: 2970 AN: 4796

European-Finnish (FIN) AF: 0.657 AC: 6917 AN: 10532

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.572 AC: 38693 AN: 67698

Other (OTH) AF: 0.538 AC: 1129 AN: 2098

Alfa AF: 0.552 Hom.: 61322

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

Submissions by phenotype

not specified Benign:6

-

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. -

-

PreventionGenetics, part of Exact Sciences

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

- -

May 17, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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

- -

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

- -

Jul 22, 2021

Genome-Nilou Lab

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. -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-0.25
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9648691; hg19: chr7-148106490; COSMIC: COSV62182670;