rs4725736

Variant names:

• chr7-147481482-C-A
• rs4725736
• NM_014141.6:c.1671-4453C>A

Variant summary

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

The NM_014141.6(CNTNAP2):​c.1671-4453C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 152,068 control chromosomes in the GnomAD database, including 29,361 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 0.62 (29361 hom., cov: 33)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1671-4453C>A		intron_variant	Intron 10 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1671-4453C>A		intron_variant	Intron 10 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1671-4453C>A		intron_variant	Intron 10 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.618 AC: 93973 AN: 151950 Hom.: 29328 Cov.: 33

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.611

Gnomad OTH AF: 0.562

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

GnomAD4 genome AF: 0.618 AC: 94048 AN: 152068 Hom.: 29361 Cov.: 33 AF XY: 0.614 AC XY: 45650 AN XY: 74330

African (AFR) AF: 0.686 AC: 28446 AN: 41486

American (AMR) AF: 0.584 AC: 8924 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1897 AN: 3466

East Asian (EAS) AF: 0.508 AC: 2626 AN: 5168

South Asian (SAS) AF: 0.547 AC: 2634 AN: 4818

European-Finnish (FIN) AF: 0.578 AC: 6093 AN: 10542

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41558 AN: 67980

Other (OTH) AF: 0.560 AC: 1185 AN: 2116

Alfa AF: 0.615 Hom.: 4379

Bravo AF: 0.624

Asia WGS AF: 0.510 AC: 1776 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.036
DANN	Benign	0.23
PhyloP100		-2.0
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: rs4725736; hg19: chr7-147178574;