rs2189883

Variant names:

• chr7-147991795-G-A
• rs2189883
• NM_014141.6:c.2383+13806G>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.2383+13806G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 151,922 control chromosomes in the GnomAD database, including 33,737 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 0.64 (33737 hom., cov: 31)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.201
• Publications: 6 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.2383+13806G>A		intron_variant	Intron 15 of 23	ENST00000361727.8	NP_054860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.2383+13806G>A		intron_variant	Intron 15 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000627772.2	n.556+13806G>A		intron_variant	Intron 4 of 12	2
CNTNAP2	ENST00000636870.1	n.2245+13806G>A		intron_variant	Intron 13 of 21	5
CNTNAP2	ENST00000637825.1	n.1866+13806G>A		intron_variant	Intron 12 of 13	5

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97544 AN: 151804 Hom.: 33670 Cov.: 31

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.576

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

GnomAD4 genome AF: 0.643 AC: 97676 AN: 151922 Hom.: 33737 Cov.: 31 AF XY: 0.646 AC XY: 47949 AN XY: 74204

African (AFR) AF: 0.893 AC: 37057 AN: 41492

American (AMR) AF: 0.670 AC: 10212 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1323 AN: 3466

East Asian (EAS) AF: 0.833 AC: 4292 AN: 5152

South Asian (SAS) AF: 0.498 AC: 2396 AN: 4816

European-Finnish (FIN) AF: 0.623 AC: 6549 AN: 10518

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.503 AC: 34184 AN: 67916

Other (OTH) AF: 0.575 AC: 1214 AN: 2112

Alfa AF: 0.540 Hom.: 12944

Bravo AF: 0.662

Asia WGS AF: 0.663 AC: 2301 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.55
PhyloP100		0.20
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: rs2189883; hg19: chr7-147688887;