rs7812091

Variant names:

• chr7-147043485-T-C
• rs7812091
• NM_014141.6:c.403-422T>C

Variant summary

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

The NM_014141.6(CNTNAP2):​c.403-422T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,044 control chromosomes in the GnomAD database, including 10,717 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 0.37 (10717 hom., cov: 33)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.807
• Publications: 8 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.403-422T>C		intron_variant	Intron 3 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.403-422T>C		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.403-422T>C		intron_variant	Intron 3 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56555 AN: 151926 Hom.: 10717 Cov.: 33

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.450

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.372 AC: 56571 AN: 152044 Hom.: 10717 Cov.: 33 AF XY: 0.370 AC XY: 27499 AN XY: 74328

African (AFR) AF: 0.360 AC: 14924 AN: 41478

American (AMR) AF: 0.278 AC: 4249 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1282 AN: 3468

East Asian (EAS) AF: 0.450 AC: 2323 AN: 5166

South Asian (SAS) AF: 0.439 AC: 2119 AN: 4824

European-Finnish (FIN) AF: 0.413 AC: 4369 AN: 10572

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26042 AN: 67956

Other (OTH) AF: 0.360 AC: 761 AN: 2112

Alfa AF: 0.375 Hom.: 26493

Bravo AF: 0.359

Asia WGS AF: 0.454 AC: 1568 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.2
DANN	Benign	0.57
PhyloP100		0.81
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: rs7812091; hg19: chr7-146740577;