rs3779031

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014141.6(CNTNAP2):c.3248-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 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
NM_014141.6 splice_region, intron

Scores

Splicing: ADA: 0.00001247

Clinical Significance

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

Conservation

PhyloP100: -2.39

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR, AD Classification: DEFINITIVE, NO_KNOWN Submitted by: ClinGen
cortical dysplasia-focal epilepsy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

CNTNAP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 link	c.3248-4A>G		splice_region_variant, intron_variant	Intron 19 of 23	ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 link	c.3248-4A>G		splice_region_variant, intron_variant	Intron 19 of 23	1	NM_014141.6	ENSP00000354778.3		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

GnomAD2 exomes

AF:

0.218

AC:

54774

AN:

250762

AF XY:

0.212

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 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

African (AFR)

AF:

0.140

AC:

4680

AN:

33472

American (AMR)

AF:

0.349

AC:

15597

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0847

AC:

2214

AN:

26134

East Asian (EAS)

AF:

0.312

AC:

12383

AN:

39686

South Asian (SAS)

AF:

0.213

AC:

18404

AN:

86246

European-Finnish (FIN)

AF:

0.256

AC:

13691

AN:

53382

Middle Eastern (MID)

AF:

0.120

AC:

691

AN:

5768

European-Non Finnish (NFE)

AF:

0.184

AC:

204489

AN:

1111646

Other (OTH)

AF:

0.187

AC:

11295

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

11642

23283

34925

46566

58208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.186

AC:

28322

AN:

152166

Hom.:

2955

Cov.:

AF XY:

0.192

AC XY:

14297

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.141

AC:

5861

AN:

41510

American (AMR)

AF:

0.270

AC:

4128

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0851

AC:

295

AN:

3468

East Asian (EAS)

AF:

0.325

AC:

1684

AN:

5180

South Asian (SAS)

AF:

0.238

AC:

1149

AN:

4818

European-Finnish (FIN)

AF:

0.263

AC:

2791

AN:

10594

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.175

AC:

11905

AN:

67982

Other (OTH)

AF:

0.186

AC:

392

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1149

2299

3448

4598

5747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.178

Hom.:

5042

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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 17, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cortical dysplasia-focal epilepsy syndrome

Benign:3

Apr 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Pitt-Hopkins-like syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 22, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.015

(source)

DANN

Benign

0.39

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs3779031

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over