chr7-147977856-A-T

Variant names:

• chr7-147977856-A-T
• rs10240482
• NM_014141.6:c.2256-6A>T

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.2256-6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0673 in 1,612,480 control chromosomes in the GnomAD database, including 4,888 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1088 hom., cov: 31)
  • Exomes 𝑓: 0.064 (3800 hom.)
• Consequence: CNTNAP2 NM_014141.6 splice_region, intron
• Scores: Splicing: ADA: 0.0004320
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.433
• Publications: 12 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=-0.72).
• BP6: Variant 7-147977856-A-T is Benign according to our data. Variant chr7-147977856-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014141.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.2256-6A>T		splice_region intron	N/A	NP_054860.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.2256-6A>T		splice_region intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000455301.2	TSL:3	n.191-6A>T		splice_region intron	N/A
	CNTNAP2	ENST00000627772.2	TSL:2	n.429-6A>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15811 AN: 151980 Hom.: 1091 Cov.: 31

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0661

Gnomad ASJ AF: 0.0876

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0485

Gnomad FIN AF: 0.0689

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0599

Gnomad OTH AF: 0.0967

GnomAD2 exomes AF: 0.0774 AC: 19470 AN: 251400 AF XY: 0.0734

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0567

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.184

Gnomad FIN exome AF: 0.0641

Gnomad NFE exome AF: 0.0591

Gnomad OTH exome AF: 0.0719

GnomAD4 exome AF: 0.0635 AC: 92739 AN: 1460382 Hom.: 3800 Cov.: 33 AF XY: 0.0629 AC XY: 45677 AN XY: 726598

African (AFR) AF: 0.206 AC: 6877 AN: 33392

American (AMR) AF: 0.0585 AC: 2618 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0803 AC: 2098 AN: 26128

East Asian (EAS) AF: 0.176 AC: 7000 AN: 39682

South Asian (SAS) AF: 0.0476 AC: 4102 AN: 86236

European-Finnish (FIN) AF: 0.0624 AC: 3331 AN: 53408

Middle Eastern (MID) AF: 0.0720 AC: 414 AN: 5748

European-Non Finnish (NFE) AF: 0.0556 AC: 61771 AN: 1110732

Other (OTH) AF: 0.0750 AC: 4528 AN: 60334

GnomAD4 genome AF: 0.104 AC: 15823 AN: 152098 Hom.: 1088 Cov.: 31 AF XY: 0.103 AC XY: 7648 AN XY: 74380

African (AFR) AF: 0.201 AC: 8314 AN: 41458

American (AMR) AF: 0.0660 AC: 1008 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 304 AN: 3470

East Asian (EAS) AF: 0.175 AC: 903 AN: 5174

South Asian (SAS) AF: 0.0490 AC: 236 AN: 4818

European-Finnish (FIN) AF: 0.0689 AC: 730 AN: 10590

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0599 AC: 4075 AN: 67998

Other (OTH) AF: 0.0953 AC: 201 AN: 2110

Alfa AF: 0.0710 Hom.: 167

Bravo AF: 0.110

Asia WGS AF: 0.115 AC: 400 AN: 3478

EpiCase AF: 0.0602

EpiControl AF: 0.0599

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 27, 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

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Aug 17, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Cortical dysplasia-focal epilepsy syndrome Benign:2

Jan 13, 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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		0.43
Mutation Taster		=80/20	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00043
dbscSNV1_RF	Benign	0.036
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: rs10240482; hg19: chr7-147674948; COSMIC: COSV62158216;