rs34592169

Variant names:

• chr7-147395769-G-A
• rs34592169
• NM_014141.6:c.1659G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-147395769-G-A
• chr7-147395769-G-C
• chr7-147395769-G-T

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.1659G>A​(p.Ala553Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,611,650 control chromosomes in the GnomAD database, including 42,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2847 hom., cov: 31)
  • Exomes 𝑓: 0.22 (39273 hom.)
• Consequence: CNTNAP2 NM_014141.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.49
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 7-147395769-G-A is Benign according to our data. Variant chr7-147395769-G-A is described in ClinVar as Benign. ClinVar VariationId is 95556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1659G>A	p.Ala553Ala	synonymous_variant	Exon 10 of 24	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1659G>A	p.Ala553Ala	synonymous_variant	Exon 10 of 14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1659G>A	p.Ala553Ala	synonymous_variant	Exon 10 of 24	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26108 AN: 151834 Hom.: 2845 Cov.: 31

Gnomad AFR AF: 0.0540

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.190 AC: 47523 AN: 250644 AF XY: 0.189

Gnomad AFR exome AF: 0.0487

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.00321

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.200

GnomAD4 exome AF: 0.224 AC: 327414 AN: 1459698 Hom.: 39273 Cov.: 33 AF XY: 0.222 AC XY: 161025 AN XY: 726140

African (AFR) AF: 0.0472 AC: 1575 AN: 33386

American (AMR) AF: 0.198 AC: 8844 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4613 AN: 26038

East Asian (EAS) AF: 0.00194 AC: 77 AN: 39674

South Asian (SAS) AF: 0.132 AC: 11365 AN: 86210

European-Finnish (FIN) AF: 0.255 AC: 13606 AN: 53384

Middle Eastern (MID) AF: 0.141 AC: 808 AN: 5742

European-Non Finnish (NFE) AF: 0.247 AC: 274256 AN: 1110368

Other (OTH) AF: 0.204 AC: 12270 AN: 60284

GnomAD4 genome AF: 0.172 AC: 26115 AN: 151952 Hom.: 2847 Cov.: 31 AF XY: 0.172 AC XY: 12786 AN XY: 74216

African (AFR) AF: 0.0538 AC: 2236 AN: 41526

American (AMR) AF: 0.179 AC: 2730 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 605 AN: 3470

East Asian (EAS) AF: 0.00524 AC: 27 AN: 5156

South Asian (SAS) AF: 0.124 AC: 598 AN: 4826

European-Finnish (FIN) AF: 0.278 AC: 2925 AN: 10536

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16433 AN: 67914

Other (OTH) AF: 0.156 AC: 330 AN: 2110

Alfa AF: 0.194 Hom.: 1708

Bravo AF: 0.160

Asia WGS AF: 0.0740 AC: 256 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.222

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

Cortical dysplasia-focal epilepsy syndrome Benign:3

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34592169; hg19: chr7-147092861; COSMIC: COSV62208420;