NM_014141.6:c.402+3740T>A

Variant names:

• chr7-146843644-T-A
• rs726749
• NM_014141.6:c.402+3740T>A

Variant summary

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

The NM_014141.6(CNTNAP2):​c.402+3740T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 149,998 control chromosomes in the GnomAD database, including 341 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 0.037 (341 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 1 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 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.402+3740T>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.402+3740T>A		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000636561.1	TSL:5	n.305+3740T>A		intron	N/A
	CNTNAP2	ENST00000637150.1	TSL:5	n.331+3740T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5566 AN: 149924 Hom.: 340 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000631

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0170

Gnomad NFE AF: 0.000724

Gnomad OTH AF: 0.0276

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

GnomAD4 genome AF: 0.0372 AC: 5576 AN: 149998 Hom.: 341 Cov.: 32 AF XY: 0.0358 AC XY: 2612 AN XY: 73060

African (AFR) AF: 0.127 AC: 5185 AN: 40940

American (AMR) AF: 0.0148 AC: 223 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000632 AC: 3 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9712

Middle Eastern (MID) AF: 0.0147 AC: 4 AN: 272

European-Non Finnish (NFE) AF: 0.000725 AC: 49 AN: 67626

Other (OTH) AF: 0.0274 AC: 57 AN: 2082

Alfa AF: 0.0290 Hom.: 18

Bravo AF: 0.0423

Asia WGS AF: 0.00722 AC: 25 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.13
DANN	Benign	0.66
PhyloP100		-2.0
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: rs726749; hg19: chr7-146540736;