rs34592169

chr7-147395769-G-Achr7-147395769-G-T

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.1659G>A(p.Ala553=) 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:12
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 95556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-147395769-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.1659G>A	p.Ala553=	synonymous_variant	10/24	ENST00000361727.8
CNTNAP2	XM_017011950.3	c.1659G>A	p.Ala553=	synonymous_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1659G>A	p.Ala553=	synonymous_variant	10/24	1	NM_014141.6	P1

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

GnomAD3 exomes AF: 0.190 AC: 47523 AN: 250644 Hom.: 5409 AF XY: 0.189 AC XY: 25639 AN XY: 135460

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 SAS exome AF: 0.131

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

Gnomad4 AFR exome AF: 0.0472

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.204

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

Gnomad4 AFR AF: 0.0538

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.174

Gnomad4 EAS AF: 0.00524

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.156

Alfa AF: 0.195 Hom.: 1707

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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)	Aug 16, 2012	- -
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	-	- -

Cortical dysplasia-focal epilepsy syndrome Benign:3

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -

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. -

Pitt-Hopkins-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	12
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs34592169; hg19: chr7-147092861; COSMIC: COSV62208420;