rs10251794

Variant names:

• chr7-146988457-T-A
• rs10251794
• NM_014141.6:c.403-55450T>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.403-55450T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 151,990 control chromosomes in the GnomAD database, including 5,628 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 0.26 (5628 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 7 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=-0.72).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.403-55450T>A		intron_variant	Intron 3 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.403-55450T>A		intron_variant	Intron 3 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.403-55450T>A		intron_variant	Intron 3 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39177 AN: 151874 Hom.: 5620 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.258 AC: 39217 AN: 151990 Hom.: 5628 Cov.: 32 AF XY: 0.261 AC XY: 19418 AN XY: 74280

African (AFR) AF: 0.140 AC: 5807 AN: 41500

American (AMR) AF: 0.273 AC: 4169 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3470

East Asian (EAS) AF: 0.228 AC: 1175 AN: 5144

South Asian (SAS) AF: 0.325 AC: 1564 AN: 4816

European-Finnish (FIN) AF: 0.395 AC: 4164 AN: 10548

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20302 AN: 67926

Other (OTH) AF: 0.273 AC: 576 AN: 2108

Alfa AF: 0.282 Hom.: 791

Bravo AF: 0.245

Asia WGS AF: 0.281 AC: 977 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.77
PhyloP100		1.8
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: rs10251794; hg19: chr7-146685549;