rs3779032

Positions:

• chr7-148229796-A-C
• chr7-148229796-A-G

Variant summary

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

The NM_014141.6(CNTNAP2):​c.3381+17A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,612,986 control chromosomes in the GnomAD database, including 141,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12028 hom., cov: 31)
  • Exomes 𝑓: 0.42 (129192 hom.)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.912

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=-0.86).
• BP6: Variant 7-148229796-A-C is Benign according to our data. Variant chr7-148229796-A-C is described in ClinVar as [Benign]. Clinvar id is 95567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-148229796-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.3381+17A>C		intron_variant		ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.3381+17A>C		intron_variant		1	NM_014141.6	ENSP00000354778	P1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60018 AN: 151872 Hom.: 12011 Cov.: 31

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.409

GnomAD3 exomes AF: 0.369 AC: 92427 AN: 250384 Hom.: 17763 AF XY: 0.370 AC XY: 50079 AN XY: 135448

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.324

Gnomad SAS exome AF: 0.329

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.415

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.416 AC: 607052 AN: 1460996 Hom.: 129192 Cov.: 37 AF XY: 0.412 AC XY: 299312 AN XY: 726842

Gnomad4 AFR exome AF: 0.406

Gnomad4 AMR exome AF: 0.283

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.390

Gnomad4 NFE exome AF: 0.439

Gnomad4 OTH exome AF: 0.404

GnomAD4 genome AF: 0.395 AC: 60065 AN: 151990 Hom.: 12028 Cov.: 31 AF XY: 0.392 AC XY: 29139 AN XY: 74300

Gnomad4 AFR AF: 0.409

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.272

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.393

Gnomad4 NFE AF: 0.419

Gnomad4 OTH AF: 0.411

Alfa AF: 0.380 Hom.: 2599

Bravo AF: 0.393

Asia WGS AF: 0.340 AC: 1184 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 12, 2013	- -

Cortical dysplasia-focal epilepsy syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0080
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs3779032; hg19: chr7-147926888; COSMIC: COSV62143992;