rs9648691

Positions:

• chr7-148409398-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3723G>A	p.Ala1241Ala	synonymous_variant	23/24	ENST00000361727.8	NP_054860.1
LOC105375554	XR_928094.2	n.210-14706C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3723G>A	p.Ala1241Ala	synonymous_variant	23/24	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

GnomAD3 exomes AF: 0.502 AC: 96596 AN: 192418 Hom.: 31165 AF XY: 0.512 AC XY: 53432 AN XY: 104414

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

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.: 32 AF XY: 0.571 AC XY: 42277 AN XY: 74028

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

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2013	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cortical dysplasia-focal epilepsy syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
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	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pitt-Hopkins-like syndrome Benign:1

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

Jan 08, 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	-0.38
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

Other links and lift over

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