chr7-148229642-A-G

Position:

chr7-148229642-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000361727.8(CNTNAP2):c.3248-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,586 control chromosomes in the GnomAD database, including 32,279 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2955 hom., cov: 32)

Exomes 𝑓: 0.19 ( 29324 hom. )

Consequence

CNTNAP2
ENST00000361727.8 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001247

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -2.39

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 7-148229642-A-G is Benign according to our data. Variant chr7-148229642-A-G is described in ClinVar as [Benign]. Clinvar id is 95566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148229642-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.3248-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		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.3248-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014141.6	ENSP00000354778	P1	Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28274

AN:

152048

Hom.:

2943

Cov.:

show subpopulations

Gnomad AFR

AF:

0.141

Gnomad AMI

AF:

0.0987

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.0851

Gnomad EAS

AF:

0.325

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.263

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.182

GnomAD3 exomes

AF:

0.218

AC:

54774

AN:

250762

Hom.:

6972

AF XY:

0.212

AC XY:

28743

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.363

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.322

Gnomad SAS exome

AF:

0.210

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.176

Gnomad OTH exome

AF:

0.191

GnomAD4 exome

AF:

0.194

AC:

283444

AN:

1461420

Hom.:

29324

Cov.:

AF XY:

0.193

AC XY:

140190

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.140

Gnomad4 AMR exome

AF:

0.349

Gnomad4 ASJ exome

AF:

0.0847

Gnomad4 EAS exome

AF:

0.312

Gnomad4 SAS exome

AF:

0.213

Gnomad4 FIN exome

AF:

0.256

Gnomad4 NFE exome

AF:

0.184

Gnomad4 OTH exome

AF:

0.187

GnomAD4 genome

AF:

0.186

AC:

28322

AN:

152166

Hom.:

2955

Cov.:

AF XY:

0.192

AC XY:

14297

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.141

Gnomad4 AMR

AF:

0.270

Gnomad4 ASJ

AF:

0.0851

Gnomad4 EAS

AF:

0.325

Gnomad4 SAS

AF:

0.238

Gnomad4 FIN

AF:

0.263

Gnomad4 NFE

AF:

0.175

Gnomad4 OTH

AF:

0.186

Alfa

AF:

0.178

Hom.:

1936

Bravo

AF:

0.187

Asia WGS

AF:

0.277

AC:

963

AN:

3478

EpiCase

AF:

0.159

EpiControl

AF:

0.162

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cortical dysplasia-focal epilepsy syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.015

DANN

Benign

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.040

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