7-146116535-AT-A

Variant names:

• chr7-146116535-AT-A
• rs886062041
• ENST00000625365.2:c.-229-112delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000625365.2(CNTNAP2):​c.-229-112delT 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
• 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 -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: {Uncertain_significance=2, Benign=1}.
• 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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000625365.2	c.-229-112delT		intron_variant	Intron 1 of 3	5		ENSP00000485955.1

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

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

African (AFR) AF: 0.139 AC: 447 AN: 3210

American (AMR) AF: 0.0577 AC: 205 AN: 3550

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 159 AN: 3190

East Asian (EAS) AF: 0.0481 AC: 339 AN: 7048

South Asian (SAS) AF: 0.0487 AC: 146 AN: 2996

European-Finnish (FIN) AF: 0.0426 AC: 202 AN: 4742

Middle Eastern (MID) AF: 0.0354 AC: 14 AN: 396

European-Non Finnish (NFE) AF: 0.0463 AC: 2436 AN: 52618

Other (OTH) AF: 0.0513 AC: 285 AN: 5552

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.100 AC: 3951 AN: 39436

American (AMR) AF: 0.0110 AC: 160 AN: 14510

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3360

East Asian (EAS) AF: 0.00516 AC: 25 AN: 4842

South Asian (SAS) AF: 0.00708 AC: 32 AN: 4518

European-Finnish (FIN) AF: 0.00115 AC: 10 AN: 8700

Middle Eastern (MID) AF: 0.00368 AC: 1 AN: 272

European-Non Finnish (NFE) AF: 0.000597 AC: 39 AN: 65334

Other (OTH) AF: 0.0234 AC: 47 AN: 2006

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pitt-Hopkins-like syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.13
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs886062041; hg19: chr7-145813627; COSMIC: COSV62147084; COSMIC: COSV62147084;