rs77706740

Positions:

chr7-148383634-C-A

Variant summary

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

The NM_014141.6(CNTNAP2):c.3476-15C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,613,952 control chromosomes in the GnomAD database, including 943 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 70 hom., cov: 32)

Exomes 𝑓: 0.032 ( 873 hom. )

Consequence

CNTNAP2
NM_014141.6 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0980

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:

LOC105375554 (HGNC:):

LOC105375554 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 (BayesDel_noAF=-0.78).

BP6

Variant 7-148383634-C-A is Benign according to our data. Variant chr7-148383634-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 260349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148383634-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3824/152284) while in subpopulation NFE AF= 0.0388 (2641/68018). AF 95% confidence interval is 0.0376. There are 70 homozygotes in gnomad4. There are 1848 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.3476-15C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361727.8
LOC105375554	XR_928093.3 linkuse as main transcript	n.446-1964G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8 linkuse as main transcript	c.3476-15C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014141.6	P1	Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3823

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00767

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.0367

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0389

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0250

AC:

6288

AN:

251190

Hom.:

126

AF XY:

0.0255

AC XY:

3459

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00586

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0303

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00937

Gnomad FIN exome

AF:

0.0346

Gnomad NFE exome

AF:

0.0374

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0321

AC:

46868

AN:

1461668

Hom.:

873

Cov.:

AF XY:

0.0317

AC XY:

23020

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00445

Gnomad4 AMR exome

AF:

0.0135

Gnomad4 ASJ exome

AF:

0.0287

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00908

Gnomad4 FIN exome

AF:

0.0349

Gnomad4 NFE exome

AF:

0.0368

Gnomad4 OTH exome

AF:

0.0285

GnomAD4 genome

AF:

0.0251

AC:

3824

AN:

152284

Hom.:

Cov.:

AF XY:

0.0248

AC XY:

1848

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00772

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.0367

Gnomad4 NFE

AF:

0.0388

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0332

Hom.:

Bravo

AF:

0.0219

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.8

DANN

Benign

0.48

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

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