7-146116535-AT-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000625365.2(CNTNAP2):c.-229-102del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0374 in 227,172 control chromosomes in the GnomAD database, including 211 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.030 (198 hom., cov: 31)
  • Exomes 𝑓: 0.051 (13 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.132

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 -9 ACMG points.

• BP6: Variant 7-146116535-AT-A is Benign according to our data. Variant chr7-146116535-AT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 359164.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNTNAP2	ENST00000625365.2	c.-229-102del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4252 AN: 143810 Hom.: 199 Cov.: 31

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.00515

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00115

Gnomad MID AF: 0.00345

Gnomad NFE AF: 0.000597

Gnomad OTH AF: 0.0236

GnomAD4 exome AF: 0.0508 AC: 4233 AN: 83302 Hom.: 13 Cov.: 0 AF XY: 0.0492 AC XY: 2096 AN XY: 42628

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.0498

Gnomad4 EAS exome AF: 0.0481

Gnomad4 SAS exome AF: 0.0487

Gnomad4 FIN exome AF: 0.0426

Gnomad4 NFE exome AF: 0.0463

Gnomad4 OTH exome AF: 0.0513

GnomAD4 genome AF: 0.0297 AC: 4266 AN: 143870 Hom.: 198 Cov.: 31 AF XY: 0.0299 AC XY: 2092 AN XY: 69878

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.000298

Gnomad4 EAS AF: 0.00516

Gnomad4 SAS AF: 0.00708

Gnomad4 FIN AF: 0.00115

Gnomad4 NFE AF: 0.000597

Gnomad4 OTH AF: 0.0234

Alfa AF: 0.000669 Hom.: 1

Bravo AF: 0.0315

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pitt-Hopkins-like syndrome Uncertain:1

Uncertain significance, 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

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs886062041; hg19: chr7-145813627;