rs77706740

Variant names:

• chr7-148383634-C-A
• rs77706740
• NM_014141.6:c.3476-15C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014141.6(CNTNAP2):​c.3476-15C>A variant causes a 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 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0980
• Publications: 4 publications found

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

ENSG00000287636 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 260349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 70 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3476-15C>A		intron_variant	Intron 21 of 23	ENST00000361727.8	NP_054860.1
LOC105375554	XR_928093.3	n.446-1964G>T		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3476-15C>A		intron_variant	Intron 21 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3823 AN: 152166 Hom.: 70 Cov.: 32

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

GnomAD2 exomes AF: 0.0250 AC: 6288 AN: 251190 AF XY: 0.0255

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 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.: 33 AF XY: 0.0317 AC XY: 23020 AN XY: 727146

African (AFR) AF: 0.00445 AC: 149 AN: 33478

American (AMR) AF: 0.0135 AC: 604 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0287 AC: 750 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39664

South Asian (SAS) AF: 0.00908 AC: 783 AN: 86254

European-Finnish (FIN) AF: 0.0349 AC: 1862 AN: 53414

Middle Eastern (MID) AF: 0.0147 AC: 85 AN: 5768

European-Non Finnish (NFE) AF: 0.0368 AC: 40913 AN: 1111846

Other (OTH) AF: 0.0285 AC: 1719 AN: 60390

GnomAD4 genome AF: 0.0251 AC: 3824 AN: 152284 Hom.: 70 Cov.: 32 AF XY: 0.0248 AC XY: 1848 AN XY: 74470

African (AFR) AF: 0.00772 AC: 321 AN: 41560

American (AMR) AF: 0.0173 AC: 265 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4828

European-Finnish (FIN) AF: 0.0367 AC: 389 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0388 AC: 2641 AN: 68018

Other (OTH) AF: 0.0345 AC: 73 AN: 2114

Alfa AF: 0.0332 Hom.: 20

Bravo AF: 0.0219

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Benign:2

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pitt-Hopkins-like syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		0.098
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs77706740; hg19: chr7-148080726;