chr17-41757648-C-T

Position:

chr17-41757648-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1

The NM_002230.4(JUP):c.1910G>A(p.Arg637His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

JUP
NM_002230.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.117

Variant links:

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

JUP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09984657).

BP6

Variant 17-41757648-C-T is Benign according to our data. Variant chr17-41757648-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41757648-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000256 (39/152168) while in subpopulation AFR AF= 0.000893 (37/41448). AF 95% confidence interval is 0.000666. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4 linkuse as main transcript	c.1910G>A	p.Arg637His	missense_variant	11/14	ENST00000393931.8	NP_002221.1	P14923A0A0S2Z487

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
JUP	ENST00000393931.8 linkuse as main transcript	c.1910G>A	p.Arg637His	missense_variant	11/14	1	NM_002230.4	ENSP00000377508.3	P14923
JUP	ENST00000310706.9 linkuse as main transcript	c.1910G>A	p.Arg637His	missense_variant	11/15	1		ENSP00000311113.5	P14923
JUP	ENST00000393930.5 linkuse as main transcript	c.1910G>A	p.Arg637His	missense_variant	11/15	5		ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000685

AC:

AN:

248048

Hom.:

AF XY:

0.0000670

AC XY:

AN XY:

134386

show subpopulations

Gnomad AFR exome

AF:

0.000943

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461248

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726890

show subpopulations

Gnomad4 AFR exome

AF:

0.000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000256

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.000893

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2014	Arg637His in exon 11 of JUP: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , multiple mammals have a histidine (His) at this position despite high nearby a mino acid conservation. In addition, computational prediction tools do not sugge st a high likelihood of impact to the protein. It has also been identified in 3/ 4406 African American chromosomes by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/; dbSNP rs142095597). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 08, 2018

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;D

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.53

LIST_S2

Uncertain

0.94

.;.;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.083

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.42

B;B;B

Vest4

0.23

MVP

0.62

MPC

0.60

ClinPred

0.092

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.28

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