7-146116889-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014141.6(CNTNAP2):c.13C>T(p.Pro5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,393,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CNTNAP2
NM_014141.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.198

Publications

0 publications found

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 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

CNTNAP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10250613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNTNAP2	NM_014141.6 link	c.13C>T	p.Pro5Ser	missense_variant	Exon 1 of 24	ENST00000361727.8	NP_054860.1	Q9UHC6-1A0A090N7T7B2RCH4
CNTNAP2	XM_017011950.3 link	c.13C>T	p.Pro5Ser	missense_variant	Exon 1 of 14		XP_016867439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CNTNAP2	ENST00000361727.8 link	c.13C>T	p.Pro5Ser	missense_variant	Exon 1 of 24	1	NM_014141.6	ENSP00000354778.3	Q9UHC6-1
CNTNAP2	ENST00000625365.2 link	c.13C>T	p.Pro5Ser	missense_variant	Exon 2 of 4	5		ENSP00000485955.1	A0A0D9SES4
CNTNAP2	ENST00000637150.1 link	n.-59C>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1393806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31534

American (AMR)

AF:

0.00

AC:

AN:

35922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25102

East Asian (EAS)

AF:

0.00

AC:

AN:

35736

South Asian (SAS)

AF:

0.00

AC:

AN:

79178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5364

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1075666

Other (OTH)

AF:

0.00

AC:

AN:

57624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cortical dysplasia-focal epilepsy syndrome

Uncertain:1

Dec 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CNTNAP2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces proline with serine at codon 5 of the CNTNAP2 protein (p.Pro5Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.025

T;T;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.58

T;.;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.0

.;N;N

PhyloP100

0.20

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.76

.;N;.

REVEL

Benign

0.16

Sift

Benign

0.074

.;T;.

Sift4G

Benign

0.83

T;T;.

Polyphen

0.0

.;B;B

Vest4

0.029

MutPred

0.52

Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);

MVP

0.65

MPC

0.098

ClinPred

0.042

GERP RS

2.0

PromoterAI

-0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.044

gMVP

0.20

Mutation Taster

=87/13

polymorphism

(source)

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

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7-146116889-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over