rs61732853

chr7-146839820-C-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.318C>T(p.Ser106=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,614,084 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (68 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (60 hom.)
• Consequence: CNTNAP2 NM_014141.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.563

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=-0.41).
• BP6: Variant 7-146839820-C-T is Benign according to our data. Variant chr7-146839820-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-146839820-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.563 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.318C>T	p.Ser106=	synonymous_variant	3/24	ENST00000361727.8
CNTNAP2	XM_017011950.3	c.318C>T	p.Ser106=	synonymous_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.318C>T	p.Ser106=	synonymous_variant	3/24	1	NM_014141.6	P1

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2517 AN: 152086 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00511 AC: 1284 AN: 251450 Hom.: 22 AF XY: 0.00408 AC XY: 554 AN XY: 135904

Gnomad AFR exome AF: 0.0557

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00239 AC: 3487 AN: 1461882 Hom.: 60 Cov.: 31 AF XY: 0.00224 AC XY: 1630 AN XY: 727238

Gnomad4 AFR exome AF: 0.0582

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000627

Gnomad4 OTH exome AF: 0.00517

GnomAD4 genome AF: 0.0167 AC: 2540 AN: 152202 Hom.: 68 Cov.: 32 AF XY: 0.0162 AC XY: 1204 AN XY: 74400

Gnomad4 AFR AF: 0.0560

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00936 Hom.: 18

Bravo AF: 0.0191

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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. -

Cortical dysplasia-focal epilepsy syndrome Benign:2

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	- -

Pitt-Hopkins-like syndrome Benign:1

Likely 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

Mar 21, 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. -

Autism, susceptibility to, 15;C2750246:Cortical dysplasia-focal epilepsy syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
Cadd	Benign	13
Dann	Benign	0.67

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: rs61732853; hg19: chr7-146536912;