7-146463186-A-G

Variant names:

• chr7-146463186-A-G
• rs7805539
• NM_014141.6:c.98-311085A>G

Variant summary

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

The NM_014141.6(CNTNAP2):​c.98-311085A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 151,966 control chromosomes in the GnomAD database, including 29,049 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 0.58 (29049 hom., cov: 31)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.647
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014141.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	NM_014141.6	MANE Select	c.98-311085A>G		intron	N/A	NP_054860.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000361727.8	TSL:1 MANE Select	c.98-311085A>G		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000625365.2	TSL:5	c.98-311085A>G		intron	N/A	ENSP00000485955.1
	CNTNAP2	ENST00000637150.1	TSL:5	n.27-311085A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88851 AN: 151848 Hom.: 29047 Cov.: 31

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.538

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.737

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.601

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

GnomAD4 genome AF: 0.585 AC: 88868 AN: 151966 Hom.: 29049 Cov.: 31 AF XY: 0.592 AC XY: 43950 AN XY: 74258

African (AFR) AF: 0.276 AC: 11471 AN: 41494

American (AMR) AF: 0.537 AC: 8177 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2504 AN: 3460

East Asian (EAS) AF: 0.738 AC: 3805 AN: 5158

South Asian (SAS) AF: 0.818 AC: 3934 AN: 4808

European-Finnish (FIN) AF: 0.767 AC: 8108 AN: 10570

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.720 AC: 48882 AN: 67930

Other (OTH) AF: 0.604 AC: 1273 AN: 2106

Alfa AF: 0.630 Hom.: 4239

Bravo AF: 0.547

Asia WGS AF: 0.721 AC: 2510 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.54
PhyloP100		0.65
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: rs7805539; hg19: chr7-146160278;