7-147977856-A-T

Position:

chr7-147977856-A-T

Variant summary

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

The NM_014141.6(CNTNAP2):c.2256-6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0673 in 1,612,480 control chromosomes in the GnomAD database, including 4,888 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1088 hom., cov: 31)

Exomes 𝑓: 0.064 ( 3800 hom. )

Consequence

CNTNAP2
NM_014141.6 splice_region, intron

Scores

Splicing: ADA: 0.0004320

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.433

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:

CNTNAP2 (HGNC:):

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=-0.72).

BP6

Variant 7-147977856-A-T is Benign according to our data. Variant chr7-147977856-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 95561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-147977856-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 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.2256-6A>T		splice_region_variant, intron_variant		ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 linkuse as main transcript	c.2256-6A>T		splice_region_variant, intron_variant		1	NM_014141.6	ENSP00000354778.3		Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15811

AN:

151980

Hom.:

1091

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0661

Gnomad ASJ

AF:

0.0876

Gnomad EAS

AF:

0.175

Gnomad SAS

AF:

0.0485

Gnomad FIN

AF:

0.0689

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0599

Gnomad OTH

AF:

0.0967

GnomAD3 exomes

AF:

0.0774

AC:

19470

AN:

251400

Hom.:

1076

AF XY:

0.0734

AC XY:

9972

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.0567

Gnomad ASJ exome

AF:

0.0811

Gnomad EAS exome

AF:

0.184

Gnomad SAS exome

AF:

0.0463

Gnomad FIN exome

AF:

0.0641

Gnomad NFE exome

AF:

0.0591

Gnomad OTH exome

AF:

0.0719

GnomAD4 exome

AF:

0.0635

AC:

92739

AN:

1460382

Hom.:

3800

Cov.:

AF XY:

0.0629

AC XY:

45677

AN XY:

726598

show subpopulations

Gnomad4 AFR exome

AF:

0.206

Gnomad4 AMR exome

AF:

0.0585

Gnomad4 ASJ exome

AF:

0.0803

Gnomad4 EAS exome

AF:

0.176

Gnomad4 SAS exome

AF:

0.0476

Gnomad4 FIN exome

AF:

0.0624

Gnomad4 NFE exome

AF:

0.0556

Gnomad4 OTH exome

AF:

0.0750

GnomAD4 genome

AF:

0.104

AC:

15823

AN:

152098

Hom.:

1088

Cov.:

AF XY:

0.103

AC XY:

7648

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.201

Gnomad4 AMR

AF:

0.0660

Gnomad4 ASJ

AF:

0.0876

Gnomad4 EAS

AF:

0.175

Gnomad4 SAS

AF:

0.0490

Gnomad4 FIN

AF:

0.0689

Gnomad4 NFE

AF:

0.0599

Gnomad4 OTH

AF:

0.0953

Alfa

AF:

0.0710

Hom.:

167

Bravo

AF:

0.110

Asia WGS

AF:

0.115

AC:

400

AN:

3478

EpiCase

AF:

0.0602

EpiControl

AF:

0.0599

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

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)	Mar 27, 2013	- -
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	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 17, 2017	- -

Cortical dysplasia-focal epilepsy syndrome

Benign:2

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

Pitt-Hopkins-like syndrome

Benign:1

Likely 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

-0.72

CADD

Benign

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00043

dbscSNV1_RF

Benign

0.036

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

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