rs2707592

Variant names:

• chr7-147963361-A-G
• rs2707592
• NM_014141.6:c.2256-14501A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014141.6(CNTNAP2):​c.2256-14501A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 151,996 control chromosomes in the GnomAD database, including 38,061 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (38061 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.347
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.2256-14501A>G		intron_variant	Intron 14 of 23	ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.2256-14501A>G		intron_variant	Intron 14 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.669 AC: 101673 AN: 151878 Hom.: 38053 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.941

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.875

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.707

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.669 AC: 101709 AN: 151996 Hom.: 38061 Cov.: 32 AF XY: 0.671 AC XY: 49837 AN XY: 74298

African (AFR) AF: 0.301 AC: 12485 AN: 41454

American (AMR) AF: 0.761 AC: 11595 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2768 AN: 3470

East Asian (EAS) AF: 0.737 AC: 3792 AN: 5142

South Asian (SAS) AF: 0.875 AC: 4215 AN: 4818

European-Finnish (FIN) AF: 0.752 AC: 7948 AN: 10574

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.829 AC: 56328 AN: 67986

Other (OTH) AF: 0.709 AC: 1494 AN: 2106

Alfa AF: 0.703 Hom.: 6240

Bravo AF: 0.650

Asia WGS AF: 0.781 AC: 2715 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.33
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2707592; hg19: chr7-147660453;