ENST00000625365.2:c.-229-113_-229-112insT

Variant names:

• chr7-146116535-A-AT
• rs886062041
• ENST00000625365.2:c.-229-113_-229-112insT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000625365.2(CNTNAP2):​c.-229-113_-229-112insT 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
• Publications: 0 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: AD, AR Classification: DEFINITIVE, NO_KNOWN Submitted by: ClinGen
• cortical dysplasia-focal epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000625365.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNTNAP2	ENST00000625365.2	TSL:5	c.-229-113_-229-112insT		intron	N/A	ENSP00000485955.1	A0A0D9SES4

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0238 AC: 79 AN: 3320

American (AMR) AF: 0.0272 AC: 100 AN: 3670

Ashkenazi Jewish (ASJ) AF: 0.0252 AC: 83 AN: 3292

East Asian (EAS) AF: 0.0249 AC: 182 AN: 7298

South Asian (SAS) AF: 0.0228 AC: 70 AN: 3066

European-Finnish (FIN) AF: 0.0277 AC: 136 AN: 4906

Middle Eastern (MID) AF: 0.0347 AC: 14 AN: 404

European-Non Finnish (NFE) AF: 0.0267 AC: 1452 AN: 54350

Other (OTH) AF: 0.0242 AC: 140 AN: 5776

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00281 AC: 111 AN: 39456

American (AMR) AF: 0.00131 AC: 19 AN: 14520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

East Asian (EAS) AF: 0.00186 AC: 9 AN: 4844

South Asian (SAS) AF: 0.000664 AC: 3 AN: 4518

European-Finnish (FIN) AF: 0.000688 AC: 6 AN: 8716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000428 AC: 28 AN: 65354

Other (OTH) AF: 0.00199 AC: 4 AN: 2006

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cortical dysplasia-focal epilepsy syndrome (1)
-	1	-	Pitt-Hopkins-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13
Mutation Taster		=299/1	polymorphism

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: rs886062041; hg19: chr7-145813627;