NM_014141.6:c.3716-5_3716-4insGT

Variant names:

• chr7-148409385-C-CTG
• rs60451214
• NM_014141.6:c.3716-5_3716-4insGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014141.6(CNTNAP2):​c.3716-5_3716-4insGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,581,614 control chromosomes in the GnomAD database, including 254,248 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25617 hom., cov: 33)
  • Exomes 𝑓: 0.56 (228631 hom.)
• Consequence: CNTNAP2 NM_014141.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.11
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 7-148409385-C-CTG is Benign according to our data. Variant chr7-148409385-C-CTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 468432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3716-5_3716-4insGT		splice_region_variant, intron_variant	Intron 22 of 23	ENST00000361727.8	NP_054860.1
LOC105375554	XR_928094.2	n.210-14694_210-14693insCA		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3716-6_3716-5insTG		splice_region_variant, intron_variant	Intron 22 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.574 AC: 86897 AN: 151390 Hom.: 25599 Cov.: 33

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.389 AC: 62495 AN: 160516 AF XY: 0.401

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.358

Gnomad EAS exome AF: 0.188

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.444

Gnomad OTH exome AF: 0.375

GnomAD4 exome AF: 0.559 AC: 799103 AN: 1430106 Hom.: 228631 Cov.: 32 AF XY: 0.561 AC XY: 399680 AN XY: 712872

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.662 AC: 21689 AN: 32774

American (AMR) AF: 0.311 AC: 13872 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 12057 AN: 25896

East Asian (EAS) AF: 0.355 AC: 14017 AN: 39512

South Asian (SAS) AF: 0.616 AC: 52676 AN: 85544

European-Finnish (FIN) AF: 0.652 AC: 34680 AN: 53180

Middle Eastern (MID) AF: 0.473 AC: 2698 AN: 5702

European-Non Finnish (NFE) AF: 0.567 AC: 614844 AN: 1083620

Other (OTH) AF: 0.550 AC: 32570 AN: 59270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.574 AC: 86949 AN: 151508 Hom.: 25617 Cov.: 33 AF XY: 0.570 AC XY: 42227 AN XY: 74046

African (AFR) AF: 0.659 AC: 27222 AN: 41324

American (AMR) AF: 0.393 AC: 5986 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1613 AN: 3454

East Asian (EAS) AF: 0.373 AC: 1922 AN: 5148

South Asian (SAS) AF: 0.619 AC: 2969 AN: 4800

European-Finnish (FIN) AF: 0.656 AC: 6911 AN: 10542

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.571 AC: 38657 AN: 67702

Other (OTH) AF: 0.537 AC: 1128 AN: 2102

Alfa AF: 0.461 Hom.: 1584

Asia WGS AF: 0.516 AC: 1795 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 02, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

not provided Benign:1

Nov 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CNTNAP2-related disorder Benign:1

May 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs60451214; hg19: chr7-148106477;