rs7794745

Variant names:

• chr7-146792514-A-T
• rs7794745
• NM_014141.6:c.208+18133A>T

Variant summary

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

The NM_014141.6(CNTNAP2):​c.208+18133A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 152,054 control chromosomes in the GnomAD database, including 20,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: 𝑓 0.48 (20031 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -0.242
• Publications: 71 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.208+18133A>T		intron_variant	Intron 2 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.208+18133A>T		intron_variant	Intron 2 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.208+18133A>T		intron_variant	Intron 2 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72677 AN: 151936 Hom.: 19979 Cov.: 32

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.461

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

GnomAD4 genome AF: 0.479 AC: 72789 AN: 152054 Hom.: 20031 Cov.: 32 AF XY: 0.478 AC XY: 35505 AN XY: 74308

African (AFR) AF: 0.764 AC: 31706 AN: 41488

American (AMR) AF: 0.331 AC: 5060 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1930 AN: 3470

East Asian (EAS) AF: 0.400 AC: 2067 AN: 5170

South Asian (SAS) AF: 0.408 AC: 1967 AN: 4820

European-Finnish (FIN) AF: 0.456 AC: 4808 AN: 10554

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23882 AN: 67970

Other (OTH) AF: 0.458 AC: 964 AN: 2106

Alfa AF: 0.428 Hom.: 2297

Bravo AF: 0.479

Asia WGS AF: 0.392 AC: 1364 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Autism, susceptibility to, 15 Other:1

Jan 01, 2008

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.24
DANN	Benign	0.57
PhyloP100		-0.24
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: rs7794745; hg19: chr7-146489606;