ENST00000625365.2:c.-230+126_-230+131delGGCGGC

Variant names:

• chr7-146116214-TGGCGGC-T
• rs145880908
• ENST00000625365.2:c.-230+126_-230+131delGGCGGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000625365.2(CNTNAP2):​c.-230+126_-230+131delGGCGGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 151,762 control chromosomes in the GnomAD database, including 75,094 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 1.0 (74872 hom., cov: 0)
  • Exomes 𝑓: 0.80 (222 hom.)
• Consequence: CNTNAP2 ENST00000625365.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.69
• 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: 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 -10 ACMG points.

• BP6: Variant 7-146116214-TGGCGGC-T is Benign according to our data. Variant chr7-146116214-TGGCGGC-T is described in ClinVar as [Benign]. Clinvar id is 1263242.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000625365.2	c.-230+126_-230+131delGGCGGC		intron_variant	Intron 1 of 3	5		ENSP00000485955.1

Frequencies

GnomAD3 genomes AF: 0.995 AC: 150350 AN: 151068 Hom.: 74820 Cov.: 0

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 0.983

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.999

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.993

Gnomad OTH AF: 0.997

GnomAD4 exome AF: 0.796 AC: 468 AN: 588 Hom.: 222 AF XY: 0.774 AC XY: 325 AN XY: 420

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

African (AFR) AF: 0.800 AC: 8 AN: 10

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 10 AN: 12

East Asian (EAS) AF: 0.588 AC: 20 AN: 34

South Asian (SAS) AF: 0.939 AC: 92 AN: 98

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.766 AC: 311 AN: 406

Other (OTH) AF: 0.962 AC: 25 AN: 26

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.007221), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.995 AC: 150455 AN: 151174 Hom.: 74872 Cov.: 0 AF XY: 0.996 AC XY: 73522 AN XY: 73852

African (AFR) AF: 0.998 AC: 41181 AN: 41262

American (AMR) AF: 0.997 AC: 15220 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 3408 AN: 3466

East Asian (EAS) AF: 0.991 AC: 4876 AN: 4918

South Asian (SAS) AF: 0.997 AC: 4757 AN: 4770

European-Finnish (FIN) AF: 0.999 AC: 10534 AN: 10544

Middle Eastern (MID) AF: 1.00 AC: 292 AN: 292

European-Non Finnish (NFE) AF: 0.993 AC: 67183 AN: 67646

Other (OTH) AF: 0.997 AC: 2097 AN: 2104

Alfa AF: 0.993 Hom.: 2203

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145880908; hg19: chr7-145813306;