7-147018769-C-T

Variant names:

• chr7-147018769-C-T
• rs1024676
• NM_014141.6:c.403-25138C>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.403-25138C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 151,736 control chromosomes in the GnomAD database, including 10,570 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 (10570 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.95
• Publications: 10 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 (SAS) allele frequency at 95% confidence interval = 0.423 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.403-25138C>T		intron_variant	Intron 3 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.403-25138C>T		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.403-25138C>T		intron_variant	Intron 3 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56092 AN: 151618 Hom.: 10569 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.370 AC: 56109 AN: 151736 Hom.: 10570 Cov.: 32 AF XY: 0.367 AC XY: 27205 AN XY: 74150

African (AFR) AF: 0.372 AC: 15430 AN: 41460

American (AMR) AF: 0.268 AC: 4086 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1285 AN: 3472

East Asian (EAS) AF: 0.423 AC: 2175 AN: 5138

South Asian (SAS) AF: 0.438 AC: 2110 AN: 4816

European-Finnish (FIN) AF: 0.411 AC: 4344 AN: 10562

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25421 AN: 67746

Other (OTH) AF: 0.358 AC: 753 AN: 2102

Alfa AF: 0.371 Hom.: 1762

Bravo AF: 0.357

Asia WGS AF: 0.439 AC: 1524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.13
DANN	Benign	0.53
PhyloP100		-1.9
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: rs1024676; hg19: chr7-146715861;