Variant 17-41763114-C-T details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022318065).

BP6

Variant 17-41763114-C-T is Benign according to our data. Variant chr17-41763114-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}. Variant chr17-41763114-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000348 (53/152326) while in subpopulation AMR AF= 0.000719 (11/15304). AF 95% confidence interval is 0.000444. There are 0 homozygotes in gnomad4. There are 24 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.1366G>A	p.Val456Ile	missense_variant	8/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
JUP	ENST00000393931.8 linkuse as main transcript	c.1366G>A	p.Val456Ile	missense_variant	8/14	1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9 linkuse as main transcript	c.1366G>A	p.Val456Ile	missense_variant	8/15	1		ENSP00000311113	P1
JUP	ENST00000393930.5 linkuse as main transcript	c.1366G>A	p.Val456Ile	missense_variant	8/15	5		ENSP00000377507	P1
JUP	ENST00000585793.1 linkuse as main transcript			upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

53

AN:

152208

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000275

AC:

69

AN:

251292

Hom.:

0

AF XY:

0.000287

AC XY:

39

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000475

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000280

AC:

410

AN:

1461870

Hom.:

0

Cov.:

32

AF XY:

0.000303

AC XY:

220

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000334

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000348

AC:

53

AN:

152326

Hom.:

0

Cov.:

32

AF XY:

0.000322

AC XY:

24

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000346

Hom.:

0

Bravo

AF:

0.000431

TwinsUK

AF:

0.000270

AC:

1

ALSPAC

AF:

0.000778

AC:

3

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000465

AC:

4

ExAC

AF:

0.000296

AC:

36

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

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	Dec 08, 2022	Variant summary: JUP c.1366G>A (p.Val456Ile) results in a conservative amino acid change located in the Armadillo region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251292 control chromosomes. The observed variant frequency is approximately 10.98 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1366G>A has been reported in the literature in one individual affected with peripartum cardiomyopathy who also carried two truncating mutations in other cardiomyopathy-causing genes (TTN, DSP; Csanyi_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: three submitters classified as likely benign while three classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 07, 2016	p.Val456Ile in exon 8 of JUP: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, 11 species, including the chimp, marmoset, dolphin and killer whale have an i soleucine (Ile) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of im pact to the protein. It has been identified in 33/66682 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 78437817). -

Naxos disease

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Arrhythmogenic right ventricular cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Blueprint Genetics

Aug 04, 2014

- -

Arrhythmogenic right ventricular dysplasia 12

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 456 of the JUP protein (p.Val456Ile). This variant is present in population databases (rs78437817, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 180375). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 04, 2021

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 08, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.41

T

BayesDel_noAF

Benign

-0.44

CADD

Benign

15

DANN

Benign

0.86

DEOGEN2

Benign

0.22

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.69

D

LIST_S2

Benign

0.64

.;.;T

M_CAP

Benign

0.015

T

MetaRNN

Benign

0.022

T;T;T

MetaSVM

Benign

-1.0

T

MutationAssessor

Benign

1.6

L;L;L

MutationTaster

Benign

0.96

D;D;D;D

PrimateAI

Benign

0.46

T

PROVEAN

Benign

-0.56

N;N;N

REVEL

Benign

0.083

Sift

Benign

0.53

T;T;T

Sift4G

Benign

0.56

T;T;T

Polyphen

0.014

B;B;B

Vest4

0.39

MVP

0.31

MPC

0.40

ClinPred

0.012

T

GERP RS

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.12

gMVP

0.15

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.

17-41763114-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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