7-147977962-G-T

Position:

chr7-147977962-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014141.6(CNTNAP2):c.2356G>T(p.Val786Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00215 in 1,614,102 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00099 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 77 hom. )

Consequence

CNTNAP2
NM_014141.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.39

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008039713).

BP6

Variant 7-147977962-G-T is Benign according to our data. Variant chr7-147977962-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 194530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000985 (150/152262) while in subpopulation SAS AF= 0.0236 (114/4824). AF 95% confidence interval is 0.0201. There are 3 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.2356G>T	p.Val786Leu	missense_variant	15/24	ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 linkuse as main transcript	c.2356G>T	p.Val786Leu	missense_variant	15/24	1	NM_014141.6	ENSP00000354778	P1	Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.000999

AC:

152

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00696

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00372

AC:

936

AN:

251428

Hom.:

AF XY:

0.00501

AC XY:

681

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00185

Gnomad SAS exome

AF:

0.0291

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00227

AC:

3320

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00306

AC XY:

2222

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0179

Gnomad4 SAS exome

AF:

0.0284

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00229

GnomAD4 genome

AF:

0.000985

AC:

150

AN:

152262

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00697

Gnomad4 SAS

AF:

0.0236

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000230

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00449

AC:

545

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -

Cortical dysplasia-focal epilepsy syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2017

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

Likely 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

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

CNTNAP2: BS1, BS2 -

CNTNAP2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.088

T;T

Eigen

Benign

-0.060

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.47

N;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.63

N;.

REVEL

Benign

0.21

Sift

Benign

1.0

T;.

Sift4G

Benign

0.72

T;.

Polyphen

0.29

B;B

Vest4

0.64

MutPred

0.43

Gain of disorder (P = 0.1464);Gain of disorder (P = 0.1464);

MVP

0.53

MPC

0.11

ClinPred

0.040

GERP RS

5.6

Varity_R

0.16

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over