rs201326295

Positions:

chr7-147044019-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_014141.6(CNTNAP2):c.515T>C(p.Ile172Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

CNTNAP2
NM_014141.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 5.00

Variant links:

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 links:

CNTNAP2 (HGNC:):

CNTNAP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022970676).

BP6

Variant 7-147044019-T-C is Benign according to our data. Variant chr7-147044019-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205308.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 linkuse as main transcript	c.515T>C	p.Ile172Thr	missense_variant	4/24	ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4
CNTNAP2	XM_017011950.3 linkuse as main transcript	c.515T>C	p.Ile172Thr	missense_variant	4/14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTNAP2	ENST00000361727.8 linkuse as main transcript	c.515T>C	p.Ile172Thr	missense_variant	4/24	1	NM_014141.6	ENSP00000354778.3		Q9UHC6-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00501

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000445

AC:

112

AN:

251442

Hom.:

AF XY:

0.000486

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00555

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000116

AC:

169

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00335

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000197

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00482

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000298

ExAC

AF:

0.000436

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2017

p.I172T (ATT>ACT): c.515T>C in CNTNAP2 gene (NM_014141.5). The Ile172Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Isoleucine residue is replaced by a polar Threonine residue. It alters a position in the F5/8 type C domain of the protein that is conserved through mammals, but Threonine is observed at this position in more distant species in evolution. Missense mutations have not been reported in this region of the protein, and multiple in silico algorithms predict Ile172Thr is likely benign. The identification of Ile172Thr an unaffected parent provided additional evidence to suggest that this variant is benign; however, the possibility that it is a disease-causing mutation cannot be excluded, as heterozygous mutations in CNTNAP2 have been identified in unaffected individuals, demonstrating incomplete penetrance (Elia et al., 2010; Gregor et al., 2011; Bakkaloglu et al., 2008; O'Roak et al., 2011; Mefford et al., 2010; Poot et al., 2010). The variant is found in INFANT-EPI,EPILEPSY panel(s). -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Pathogenic

0.85

D;D

Eigen

Benign

-0.0033

Eigen_PC

Benign

-0.020

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.74

.;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.023

T;T

MetaSVM

Pathogenic

0.97

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.2

D;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.025

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

0.54

P;P

Vest4

0.76

MVP

0.93

MPC

0.47

ClinPred

0.24

GERP RS

4.3

Varity_R

0.48

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over