rs1391540245

chr7-148118230-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014141.6(CNTNAP2):c.2497del(p.Trp833GlyfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.622

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-148118230-CT-C is Pathogenic according to our data. Variant chr7-148118230-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 536312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6	c.2497del	p.Trp833GlyfsTer18	frameshift_variant	16/24	ENST00000361727.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.2497del	p.Trp833GlyfsTer18	frameshift_variant	16/24	1	NM_014141.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 27, 2021	The homozygous c.2497del (p.Trp833GlyfsTer18) variant identified in the CNTNAP2 gene is the deletion of a single nucleotide resulting in the frameshift of the protein at amino acid 833/1332 (exon 16/24). This variant is found with low frequency in gnomAD(v3.1.1) (2 heterozygotes, 0 homozygotes; allelefrequency:1.31e-5) suggesting it is not a common benign variant in the populations represented in that database. The c.2497del (p.Trp833GlyfsTer18) variant isreported in ClinVar as Pathogenic (VarID:536312) and to our current knowledge has not been reported in affected individuals in the literature, although nonsense and frameshift variants downstream of this one have been reported in affected individuals [PMID:27439707]. Given its deleterious nature and absence in population databases, the homozygous c.2497del (p.Trp833GlyfsTer18) variant identified in the CNTNAP2 gene is reported as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This sequence change creates a premature translational stop signal (p.Trp833Glyfs*18) in the CNTNAP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNTNAP2 are known to be pathogenic (PMID: 19896112, 21827697, 25045150, 26843181, 27439707). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CNTNAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 536312). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

The c.2497delT (p.W833Gfs*18) alteration, located in exon 16 (coding exon 16) of the CNTNAP2 gene, consists of a deletion of one nucleotide at position 2497, causing a translational frameshift with a predicted alternate stop codon after 18 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 23, 2022

Frameshift variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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: rs1391540245; hg19: chr7-147815322;