NM_014141.6:c.3716-7_3716-6insTT

Variant names:

• chr7-148409383-C-CTT
• rs72268642
• NM_014141.6:c.3716-7_3716-6insTT

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.3716-7_3716-6insTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,578,214 control chromosomes in the GnomAD database, including 252,035 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25625 hom., cov: 33)
  • Exomes 𝑓: 0.56 (226410 hom.)
• Consequence: CNTNAP2 NM_014141.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.173
• Publications: 3 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 7-148409383-C-CTT is Benign according to our data. Variant chr7-148409383-C-CTT is described in ClinVar as Benign. ClinVar VariationId is 516869.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.3716-7_3716-6insTT		splice_region_variant, intron_variant	Intron 22 of 23	ENST00000361727.8	NP_054860.1
LOC105375554	XR_928094.2	n.210-14692_210-14691insAA		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3716-8_3716-7insTT		splice_region_variant, intron_variant	Intron 22 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.574 AC: 86906 AN: 151482 Hom.: 25607 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: 0.618

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.293 AC: 59553 AN: 203228 AF XY: 0.303

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.0826

Gnomad ASJ exome AF: 0.273

Gnomad EAS exome AF: 0.134

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.556 AC: 793079 AN: 1426614 Hom.: 226410 Cov.: 30 AF XY: 0.558 AC XY: 396955 AN XY: 711266

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

African (AFR) AF: 0.659 AC: 21506 AN: 32632

American (AMR) AF: 0.310 AC: 13837 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 12007 AN: 25858

East Asian (EAS) AF: 0.354 AC: 13972 AN: 39460

South Asian (SAS) AF: 0.615 AC: 52508 AN: 85412

European-Finnish (FIN) AF: 0.652 AC: 34598 AN: 53084

Middle Eastern (MID) AF: 0.473 AC: 2697 AN: 5702

European-Non Finnish (NFE) AF: 0.564 AC: 609584 AN: 1080750

Other (OTH) AF: 0.547 AC: 32370 AN: 59146

⚠️ 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: 86958 AN: 151600 Hom.: 25625 Cov.: 33 AF XY: 0.570 AC XY: 42224 AN XY: 74094

African (AFR) AF: 0.658 AC: 27225 AN: 41346

American (AMR) AF: 0.392 AC: 5982 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1614 AN: 3458

East Asian (EAS) AF: 0.373 AC: 1920 AN: 5146

South Asian (SAS) AF: 0.618 AC: 2968 AN: 4804

European-Finnish (FIN) AF: 0.654 AC: 6905 AN: 10554

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

European-Non Finnish (NFE) AF: 0.571 AC: 38676 AN: 67742

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

Alfa AF: 0.457 Hom.: 2530

Asia WGS AF: 0.515 AC: 1794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Benign:2

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
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: rs72268642; hg19: chr7-148106475;