Variant chr14-23570953-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001146028.2(JPH4):c.1778C>G(p.Ala593Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000329 in 1,518,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

JPH4
NM_001146028.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.306

Variant links:

Genes affected

JPH4 (HGNC:20156): (junctophilin 4) This gene encodes a member of the junctophilin family of transmembrane proteins that are involved in the formation of the junctional membrane complexes between the plasma membrane and the endoplasmic/sarcoplasmic reticulum in excitable cells. The encoded protein contains a conserved N-terminal repeat region called the membrane occupation and recognition nexus sequence that is found in other members of the junctophilin family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

JPH4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052579135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH4	NM_001146028.2 link	c.1778C>G	p.Ala593Gly	missense_variant	5/6	ENST00000356300.9	NP_001139500.1	Q96JJ6
JPH4	NM_032452.3 link	c.1778C>G	p.Ala593Gly	missense_variant	6/7		NP_115828.2	Q96JJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
JPH4	ENST00000356300.9 link	c.1778C>G	p.Ala593Gly	missense_variant	5/6	1	NM_001146028.2	ENSP00000348648.4	Q96JJ6
JPH4	ENST00000397118.7 link	c.1778C>G	p.Ala593Gly	missense_variant	6/7	1		ENSP00000380307.3	Q96JJ6
JPH4	ENST00000544177.1 link	c.773C>G	p.Ala258Gly	missense_variant	3/4	2		ENSP00000439562.1	F5H1L9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000584

AC:

AN:

171296

Hom.:

AF XY:

0.0000111

AC XY:

AN XY:

90444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000689

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000293

AC:

AN:

1365898

Hom.:

Cov.:

AF XY:

0.00000598

AC XY:

AN XY:

669206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000567

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000848

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.1778C>G (p.A593G) alteration is located in exon 6 (coding exon 4) of the JPH4 gene. This alteration results from a C to G substitution at nucleotide position 1778, causing the alanine (A) at amino acid position 593 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.017

.;T;T;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.58

T;.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.053

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.3

.;N;N;N

REVEL

Benign

0.060

Sift

Benign

0.26

.;T;T;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.0, 0.0050

.;B;B;B

Vest4

0.12

MutPred

0.15

.;Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);.;

MVP

0.15

MPC

0.14

ClinPred

0.043

GERP RS

-0.023

Varity_R

0.079

gMVP

0.081

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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