7-148229642-A-G

Position:

• chr7-148229642-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000361727.8(CNTNAP2):​c.3248-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,586 control chromosomes in the GnomAD database, including 32,279 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2955 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29324 hom.)
• Consequence: CNTNAP2 ENST00000361727.8 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001247
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.39

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 7-148229642-A-G is Benign according to our data. Variant chr7-148229642-A-G is described in ClinVar as [Benign]. Clinvar id is 95566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148229642-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3248-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3248-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014141.6	ENSP00000354778	P1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28274 AN: 152048 Hom.: 2943 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.0851

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.218 AC: 54774 AN: 250762 Hom.: 6972 AF XY: 0.212 AC XY: 28743 AN XY: 135634

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.322

Gnomad SAS exome AF: 0.210

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.194 AC: 283444 AN: 1461420 Hom.: 29324 Cov.: 33 AF XY: 0.193 AC XY: 140190 AN XY: 726998

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.349

Gnomad4 ASJ exome AF: 0.0847

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.213

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.186 AC: 28322 AN: 152166 Hom.: 2955 Cov.: 32 AF XY: 0.192 AC XY: 14297 AN XY: 74402

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.270

Gnomad4 ASJ AF: 0.0851

Gnomad4 EAS AF: 0.325

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.186

Alfa AF: 0.178 Hom.: 1936

Bravo AF: 0.187

Asia WGS AF: 0.277 AC: 963 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.162

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cortical dysplasia-focal epilepsy syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2016

This alteration is classified as 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. -

Pitt-Hopkins-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.015
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3779031; hg19: chr7-147926734; COSMIC: COSV62158062;