7-146116535-A-AT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The ENST00000625365.2(CNTNAP2):c.-229-102dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 230,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.026 (0 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0262 (2256/86082) while in subpopulation MID AF= 0.0347 (14/404). AF 95% confidence interval is 0.0256. There are 0 homozygotes in gnomad4_exome. There are 1163 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-229-102dup		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 173 AN: 143886 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00185

Gnomad SAS AF: 0.000661

Gnomad FIN AF: 0.000688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000428

Gnomad OTH AF: 0.00201

GnomAD4 exome AF: 0.0262 AC: 2256 AN: 86082 Hom.: 0 Cov.: 0 AF XY: 0.0264 AC XY: 1163 AN XY: 44004

Gnomad4 AFR exome AF: 0.0238

Gnomad4 AMR exome AF: 0.0272

Gnomad4 ASJ exome AF: 0.0252

Gnomad4 EAS exome AF: 0.0249

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0267

Gnomad4 OTH exome AF: 0.0242

GnomAD4 genome AF: 0.00125 AC: 180 AN: 143948 Hom.: 0 Cov.: 31 AF XY: 0.00112 AC XY: 78 AN XY: 69922

Gnomad4 AFR AF: 0.00281

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00186

Gnomad4 SAS AF: 0.000664

Gnomad4 FIN AF: 0.000688

Gnomad4 NFE AF: 0.000428

Gnomad4 OTH AF: 0.00199

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

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

- -

Computational scores

Source: dbNSFP v4.3

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: rs886062041; hg19: chr7-145813627;