7-146760775-G-C

Variant names:

• chr7-146760775-G-C
• rs10952659
• NM_014141.6:c.98-13496G>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.98-13496G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 151,404 control chromosomes in the GnomAD database, including 11,000 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 0.35 (11000 hom., cov: 29)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.84
• Publications: 2 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.98-13496G>C		intron_variant	Intron 1 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.98-13496G>C		intron_variant	Intron 1 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.98-13496G>C		intron_variant	Intron 1 of 23	1	NM_014141.6	ENSP00000354778.3
CNTNAP2	ENST00000625365.2	c.98-13496G>C		intron_variant	Intron 2 of 3	5		ENSP00000485955.1
CNTNAP2	ENST00000637150.1	n.27-13496G>C		intron_variant	Intron 1 of 8	5

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53449 AN: 151288 Hom.: 10979 Cov.: 29

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.354 AC: 53535 AN: 151404 Hom.: 11000 Cov.: 29 AF XY: 0.354 AC XY: 26132 AN XY: 73916

African (AFR) AF: 0.573 AC: 23663 AN: 41284

American (AMR) AF: 0.228 AC: 3474 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1087 AN: 3464

East Asian (EAS) AF: 0.298 AC: 1531 AN: 5136

South Asian (SAS) AF: 0.322 AC: 1534 AN: 4766

European-Finnish (FIN) AF: 0.380 AC: 3960 AN: 10422

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.255 AC: 17305 AN: 67816

Other (OTH) AF: 0.334 AC: 701 AN: 2098

Alfa AF: 0.181 Hom.: 401

Bravo AF: 0.350

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.29
DANN	Benign	0.26
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: rs10952659; hg19: chr7-146457867;