NM_014141.6:c.3381+17A>C

Variant names:

• chr7-148229796-A-C
• rs3779032
• NM_014141.6:c.3381+17A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014141.6(CNTNAP2):​c.3381+17A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,612,986 control chromosomes in the GnomAD database, including 141,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12028 hom., cov: 31)
  • Exomes 𝑓: 0.42 (129192 hom.)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.912
• Publications: 7 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-148229796-A-C is Benign according to our data. Variant chr7-148229796-A-C is described in ClinVar as Benign. ClinVar VariationId is 95567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3381+17A>C		intron_variant	Intron 20 of 23	ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3381+17A>C		intron_variant	Intron 20 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60018 AN: 151872 Hom.: 12011 Cov.: 31

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.369 AC: 92427 AN: 250384 AF XY: 0.370

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.324

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.416 AC: 607052 AN: 1460996 Hom.: 129192 Cov.: 37 AF XY: 0.412 AC XY: 299312 AN XY: 726842

African (AFR) AF: 0.406 AC: 13600 AN: 33464

American (AMR) AF: 0.283 AC: 12663 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 7105 AN: 26132

East Asian (EAS) AF: 0.274 AC: 10869 AN: 39672

South Asian (SAS) AF: 0.329 AC: 28384 AN: 86234

European-Finnish (FIN) AF: 0.390 AC: 20785 AN: 53244

Middle Eastern (MID) AF: 0.305 AC: 1762 AN: 5768

European-Non Finnish (NFE) AF: 0.439 AC: 487525 AN: 1111414

Other (OTH) AF: 0.404 AC: 24359 AN: 60356

GnomAD4 genome AF: 0.395 AC: 60065 AN: 151990 Hom.: 12028 Cov.: 31 AF XY: 0.392 AC XY: 29139 AN XY: 74300

African (AFR) AF: 0.409 AC: 16947 AN: 41434

American (AMR) AF: 0.335 AC: 5119 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 943 AN: 3462

East Asian (EAS) AF: 0.317 AC: 1638 AN: 5170

South Asian (SAS) AF: 0.339 AC: 1631 AN: 4814

European-Finnish (FIN) AF: 0.393 AC: 4164 AN: 10584

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28446 AN: 67952

Other (OTH) AF: 0.411 AC: 867 AN: 2110

Alfa AF: 0.386 Hom.: 3760

Bravo AF: 0.393

Asia WGS AF: 0.340 AC: 1184 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 12, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cortical dysplasia-focal epilepsy syndrome Benign:2

Jul 22, 2021

Genome-Nilou Lab

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

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0080
DANN	Benign	0.36
PhyloP100		-0.91
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: rs3779032; hg19: chr7-147926888; COSMIC: COSV62143992;