7-148367794-A-G

Variant names:

• chr7-148367794-A-G
• rs1637864
• NM_014141.6:c.3476-15855A>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.3476-15855A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 151,960 control chromosomes in the GnomAD database, including 40,186 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 0.72 (40186 hom., cov: 31)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65
• Publications: 4 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

ENSG00000287636 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.794 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.3476-15855A>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.3476-15855A>G		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000463592.3	TSL:1	c.-194-15855A>G		intron	N/A	ENSP00000486292.1
	CNTNAP2	ENST00000628930.2	TSL:2	c.653-15855A>G		intron	N/A	ENSP00000487516.1

Frequencies

GnomAD3 genomes AF: 0.717 AC: 108922 AN: 151842 Hom.: 40167 Cov.: 31

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.806

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.796

Gnomad OTH AF: 0.752

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

GnomAD4 genome AF: 0.717 AC: 108974 AN: 151960 Hom.: 40186 Cov.: 31 AF XY: 0.717 AC XY: 53274 AN XY: 74262

African (AFR) AF: 0.537 AC: 22250 AN: 41404

American (AMR) AF: 0.806 AC: 12306 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.804 AC: 2790 AN: 3470

East Asian (EAS) AF: 0.724 AC: 3747 AN: 5176

South Asian (SAS) AF: 0.647 AC: 3103 AN: 4794

European-Finnish (FIN) AF: 0.757 AC: 8003 AN: 10566

Middle Eastern (MID) AF: 0.784 AC: 229 AN: 292

European-Non Finnish (NFE) AF: 0.796 AC: 54133 AN: 67970

Other (OTH) AF: 0.749 AC: 1581 AN: 2112

Alfa AF: 0.771 Hom.: 10537

Bravo AF: 0.718

Asia WGS AF: 0.656 AC: 2283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.055
DANN	Benign	0.71
PhyloP100		-2.7
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: rs1637864; hg19: chr7-148064886; COSMIC: COSV62208195;