rs144056952

Positions:

chr1-205069520-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 2P and 18B. PP2PP3BP4_ModerateBP6_Very_StrongBS1BS2

The ENST00000331830.7(CNTN2):c.2155G>A(p.Gly719Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,984 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

CNTN2
ENST00000331830.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.69

Variant links:

Genes affected

CNTN2 (HGNC:2172): (contactin 2) This gene encodes a member of the contactin family of proteins, part of the immunoglobulin superfamily of cell adhesion molecules. The encoded glycosylphosphatidylinositol (GPI)-anchored neuronal membrane protein plays a role in the proliferation, migration, and axon guidance of neurons of the developing cerebellum. A mutation in this gene may be associated with adult myoclonic epilepsy. [provided by RefSeq, Sep 2016]

CNTN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNTN2. . Gene score misZ 2.5878 (greater than the threshold 3.09). Trascript score misZ 3.2882 (greater than threshold 3.09). GenCC has associacion of gene with benign adult familial myoclonic epilepsy, complex neurodevelopmental disorder, epilepsy, familial adult myoclonic, 5.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.081897855).

BP6

Variant 1-205069520-G-A is Benign according to our data. Variant chr1-205069520-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000821 (125/152232) while in subpopulation NFE AF= 0.00128 (87/68026). AF 95% confidence interval is 0.00106. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN2	NM_005076.5 linkuse as main transcript	c.2155G>A	p.Gly719Arg	missense_variant	17/23	ENST00000331830.7	NP_005067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNTN2	ENST00000331830.7 linkuse as main transcript	c.2155G>A	p.Gly719Arg	missense_variant	17/23	1	NM_005076.5	ENSP00000330633	P1

Frequencies

GnomAD3 genomes

AF:

0.000822

AC:

125

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000961

AC:

239

AN:

248588

Hom.:

AF XY:

0.000973

AC XY:

131

AN XY:

134580

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00576

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00117

AC:

1711

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

831

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.00524

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.00130

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.000821

AC:

125

AN:

152232

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00128

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00131

Hom.:

Bravo

AF:

0.00100

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.00180

EpiControl

AF:

0.00136

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CNTN2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 04, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Epilepsy, familial adult myoclonic, 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.42

T;T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.082

T;T;T

MetaSVM

Uncertain

-0.0052

MutationAssessor

Pathogenic

3.5

H;H;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.4

.;D;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;.

Vest4

0.95

MutPred

0.73

Gain of methylation at G719 (P = 0.0258);Gain of methylation at G719 (P = 0.0258);Gain of methylation at G719 (P = 0.0258);

MVP

0.92

MPC

1.4

ClinPred

0.20

GERP RS

5.6

Varity_R

0.92

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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