7-146116762-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000625365.2(CNTNAP2):c.-115G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 741,096 control chromosomes in the GnomAD database, including 97,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (18940 hom., cov: 32)
  • Exomes 𝑓: 0.51 (78432 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.230

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 7-146116762-G-A is Benign according to our data. Variant chr7-146116762-G-A is described in ClinVar as [Benign]. Clinvar id is 359171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNTNAP2	NM_014141.6			upstream_gene_variant		ENST00000361727.8
CNTNAP2	XM_017011950.3			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000625365.2	c.-115G>A		5_prime_UTR_variant	2/4	5
CNTNAP2	ENST00000361727.8			upstream_gene_variant		1	NM_014141.6	P1

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75307 AN: 151814 Hom.: 18935 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.476

GnomAD4 exome AF: 0.513 AC: 302338 AN: 589164 Hom.: 78432 Cov.: 8 AF XY: 0.515 AC XY: 156489 AN XY: 303876

Gnomad4 AFR exome AF: 0.440

Gnomad4 AMR exome AF: 0.526

Gnomad4 ASJ exome AF: 0.539

Gnomad4 EAS exome AF: 0.638

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.495

Gnomad4 OTH exome AF: 0.508

GnomAD4 genome AF: 0.496 AC: 75356 AN: 151932 Hom.: 18940 Cov.: 32 AF XY: 0.504 AC XY: 37413 AN XY: 74228

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.529

Gnomad4 EAS AF: 0.637

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.611

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.479

Alfa AF: 0.510 Hom.: 17895

Bravo AF: 0.487

Asia WGS AF: 0.541 AC: 1882 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pitt-Hopkins-like syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	16
Dann	Benign	0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs2462603; hg19: chr7-145813854;