chr7-147343214-G-A

Variant names:

• chr7-147343214-G-A
• rs1404699
• NM_014141.6:c.1498+42924G>A

Variant summary

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

The ENST00000361727.8(CNTNAP2):​c.1498+42924G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.637 in 151,928 control chromosomes in the GnomAD database, including 31,794 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 (31794 hom., cov: 32)
• Consequence: CNTNAP2 ENST00000361727.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.227
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361727.8. 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.1498+42924G>A		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.1498+42924G>A		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000636870.1	TSL:5	n.1360+42924G>A		intron	N/A
	CNTNAP2	ENST00000637694.1	TSL:5	n.1401+42924G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96668 AN: 151808 Hom.: 31761 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.547

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.566

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

GnomAD4 genome AF: 0.637 AC: 96747 AN: 151928 Hom.: 31794 Cov.: 32 AF XY: 0.633 AC XY: 46969 AN XY: 74240

African (AFR) AF: 0.807 AC: 33476 AN: 41478

American (AMR) AF: 0.587 AC: 8944 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.547 AC: 1894 AN: 3464

East Asian (EAS) AF: 0.418 AC: 2159 AN: 5160

South Asian (SAS) AF: 0.562 AC: 2703 AN: 4808

European-Finnish (FIN) AF: 0.570 AC: 6021 AN: 10566

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39679 AN: 67906

Other (OTH) AF: 0.562 AC: 1185 AN: 2110

Alfa AF: 0.587 Hom.: 19709

Bravo AF: 0.644

Asia WGS AF: 0.478 AC: 1665 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.2
DANN	Benign	0.54
PhyloP100		0.23
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: rs1404699; hg19: chr7-147040306;