rs139732336

Positions:

chr1-205061394-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_005076.5(CNTN2):c.947C>T(p.Thr316Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,612,648 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 39 hom. )

Consequence

CNTN2
NM_005076.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.17

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 -12 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.006309241).

BP6

Variant 1-205061394-C-T is Benign according to our data. Variant chr1-205061394-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474493.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00449 (684/152304) while in subpopulation NFE AF= 0.00629 (428/68010). AF 95% confidence interval is 0.0058. There are 6 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNTN2	NM_005076.5 linkuse as main transcript	c.947C>T	p.Thr316Ile	missense_variant	8/23	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.947C>T	p.Thr316Ile	missense_variant	8/23	1	NM_005076.5	ENSP00000330633	P1

Frequencies

GnomAD3 genomes

AF:

0.00449

AC:

684

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00629

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00497

AC:

1221

AN:

245696

Hom.:

AF XY:

0.00461

AC XY:

613

AN XY:

133074

show subpopulations

Gnomad AFR exome

AF:

0.00139

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00211

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000198

Gnomad FIN exome

AF:

0.0139

Gnomad NFE exome

AF:

0.00691

Gnomad OTH exome

AF:

0.00569

GnomAD4 exome

AF:

0.00601

AC:

8773

AN:

1460344

Hom.:

Cov.:

AF XY:

0.00586

AC XY:

4256

AN XY:

726338

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00287

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000500

Gnomad4 FIN exome

AF:

0.0139

Gnomad4 NFE exome

AF:

0.00669

Gnomad4 OTH exome

AF:

0.00486

GnomAD4 genome

AF:

0.00449

AC:

684

AN:

152304

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0128

Gnomad4 NFE

AF:

0.00629

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00582

Hom.:

Bravo

AF:

0.00368

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00477

AC:

579

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2017

- -

Epilepsy, familial adult myoclonic, 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.71

.;.;T

MetaRNN

Benign

0.0063

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

L;L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

.;N;.

REVEL

Benign

0.10

Sift

Benign

0.42

.;T;.

Sift4G

Benign

0.43

.;T;.

Polyphen

0.0020

B;B;.

Vest4

0.22

MVP

0.82

MPC

0.55

ClinPred

0.0062

GERP RS

2.1

Varity_R

0.13

gMVP

0.48

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