7-148409385-C-CTG

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

LOC105375554 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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

GnomAD3 exomes AF: 0.389 AC: 62495 AN: 160516 Hom.: 21425 AF XY: 0.401 AC XY: 34644 AN XY: 86376

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 SAS exome AF: 0.482

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

Gnomad4 AFR exome AF: 0.662

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.466

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.616

Gnomad4 FIN exome AF: 0.652

Gnomad4 NFE exome AF: 0.567

Gnomad4 OTH exome AF: 0.550

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

Gnomad4 AFR AF: 0.659

Gnomad4 AMR AF: 0.393

Gnomad4 ASJ AF: 0.467

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.619

Gnomad4 FIN AF: 0.656

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.537

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

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

- -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs60451214; hg19: chr7-148106477;