7-147888727-T-C

Variant names:

• chr7-147888727-T-C
• rs2538976
• NM_014141.6:c.2099-14838T>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.2099-14838T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 131,636 control chromosomes in the GnomAD database, including 14,836 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 0.44 (14836 hom., cov: 27)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.572
• Publications: 14 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 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.2099-14838T>C		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.2099-14838T>C		intron	N/A	ENSP00000354778.3
	CNTNAP2	ENST00000455301.2	TSL:3	n.34-14838T>C		intron	N/A
	CNTNAP2	ENST00000627772.2	TSL:2	n.272-14838T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.442 AC: 58186 AN: 131516 Hom.: 14826 Cov.: 27

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.559

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.488

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.475

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

GnomAD4 genome AF: 0.442 AC: 58234 AN: 131636 Hom.: 14836 Cov.: 27 AF XY: 0.437 AC XY: 27957 AN XY: 63980

African (AFR) AF: 0.462 AC: 18285 AN: 39558

American (AMR) AF: 0.448 AC: 5661 AN: 12626

Ashkenazi Jewish (ASJ) AF: 0.559 AC: 1620 AN: 2896

East Asian (EAS) AF: 0.338 AC: 1402 AN: 4154

South Asian (SAS) AF: 0.368 AC: 1386 AN: 3762

European-Finnish (FIN) AF: 0.382 AC: 3411 AN: 8938

Middle Eastern (MID) AF: 0.487 AC: 113 AN: 232

European-Non Finnish (NFE) AF: 0.445 AC: 25389 AN: 57070

Other (OTH) AF: 0.475 AC: 809 AN: 1704

Alfa AF: 0.500 Hom.: 78133

Bravo AF: 0.495

Asia WGS AF: 0.456 AC: 1590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	9.1
DANN	Benign	0.85
PhyloP100		-0.57
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: rs2538976; hg19: chr7-147585819; COSMIC: COSV62153005;