rs2538963

Variant names:

• chr7-147902354-C-T
• rs2538963
• NM_014141.6:c.2099-1211C>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.2099-1211C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,844 control chromosomes in the GnomAD database, including 10,733 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 (10733 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.921
• Publications: 5 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.2099-1211C>T		intron_variant	Intron 13 of 23	ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.2099-1211C>T		intron_variant	Intron 13 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56253 AN: 151726 Hom.: 10720 Cov.: 32

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.349

Gnomad OTH AF: 0.348

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

GnomAD4 genome AF: 0.371 AC: 56298 AN: 151844 Hom.: 10733 Cov.: 32 AF XY: 0.366 AC XY: 27121 AN XY: 74172

African (AFR) AF: 0.460 AC: 19048 AN: 41390

American (AMR) AF: 0.281 AC: 4294 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1471 AN: 3470

East Asian (EAS) AF: 0.375 AC: 1939 AN: 5168

South Asian (SAS) AF: 0.332 AC: 1596 AN: 4814

European-Finnish (FIN) AF: 0.306 AC: 3202 AN: 10468

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.349 AC: 23686 AN: 67952

Other (OTH) AF: 0.345 AC: 730 AN: 2114

Alfa AF: 0.359 Hom.: 1660

Bravo AF: 0.371

Asia WGS AF: 0.338 AC: 1175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.23
PhyloP100		-0.92
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: rs2538963; hg19: chr7-147599446;