7-147492648-C-T

Variant names:

• chr7-147492648-C-T
• rs2141388
• NM_014141.6:c.1777+6607C>T

Variant summary

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

The NM_014141.6(CNTNAP2):​c.1777+6607C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 151,934 control chromosomes in the GnomAD database, including 6,370 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 0.29 (6370 hom., cov: 32)
• Consequence: CNTNAP2 NM_014141.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6	c.1777+6607C>T		intron_variant	Intron 11 of 23	ENST00000361727.8	NP_054860.1
CNTNAP2	XM_017011950.3	c.1777+6607C>T		intron_variant	Intron 11 of 13		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8	c.1777+6607C>T		intron_variant	Intron 11 of 23	1	NM_014141.6	ENSP00000354778.3

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43524 AN: 151816 Hom.: 6355 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.356

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.287 AC: 43557 AN: 151934 Hom.: 6370 Cov.: 32 AF XY: 0.293 AC XY: 21740 AN XY: 74266

African (AFR) AF: 0.276 AC: 11424 AN: 41440

American (AMR) AF: 0.340 AC: 5187 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3470

East Asian (EAS) AF: 0.426 AC: 2192 AN: 5140

South Asian (SAS) AF: 0.323 AC: 1554 AN: 4814

European-Finnish (FIN) AF: 0.338 AC: 3560 AN: 10544

Middle Eastern (MID) AF: 0.355 AC: 103 AN: 290

European-Non Finnish (NFE) AF: 0.259 AC: 17582 AN: 67946

Other (OTH) AF: 0.318 AC: 669 AN: 2104

Alfa AF: 0.288 Hom.: 1119

Bravo AF: 0.284

Asia WGS AF: 0.398 AC: 1380 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.071
DANN	Benign	0.25
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: rs2141388; hg19: chr7-147189740;