chr8-74244858-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020647.4(JPH1):c.1576G>A(p.Val526Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00533 in 1,614,154 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 217 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 218 hom. )

Consequence

JPH1
NM_020647.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0290

Publications

5 publications found

Variant links:

Genes affected

JPH1 (HGNC:14201): (junctophilin 1) Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. This gene is a member of the junctophilin gene family. [provided by RefSeq, Jul 2008]

JPH1 Gene-Disease associations (from GenCC):

congenital myopathy 25
Inheritance: AR Classification: MODERATE Submitted by: G2P

JPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015604794).

BP6

Variant 8-74244858-C-T is Benign according to our data. Variant chr8-74244858-C-T is described in ClinVar as Benign. ClinVar VariationId is 776357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020647.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JPH1	NM_020647.4	MANE Select	c.1576G>A	p.Val526Ile	missense	Exon 4 of 6	NP_065698.1	Q9HDC5
JPH1	NM_001317830.2		c.1576G>A	p.Val526Ile	missense	Exon 4 of 6	NP_001304759.1	Q9HDC5
JPH1	NM_001363050.1		c.1576G>A	p.Val526Ile	missense	Exon 4 of 6	NP_001349979.1	Q9HDC5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
JPH1	ENST00000342232.5	TSL:1 MANE Select	c.1576G>A	p.Val526Ile	missense	Exon 4 of 6	ENSP00000344488.4	Q9HDC5
JPH1	ENST00000519947.1	TSL:1	n.*971G>A		non_coding_transcript_exon	Exon 4 of 5	ENSP00000429652.1	E5RHU9
JPH1	ENST00000519947.1	TSL:1	n.*971G>A		3_prime_UTR	Exon 4 of 5	ENSP00000429652.1	E5RHU9

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4291

AN:

152144

Hom.:

216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0986

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.00774

AC:

1946

AN:

251446

AF XY:

0.00561

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.00506

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00295

AC:

4306

AN:

1461892

Hom.:

218

Cov.:

AF XY:

0.00255

AC XY:

1858

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.105

AC:

3505

AN:

33480

American (AMR)

AF:

0.00550

AC:

246

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000255

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000133

AC:

148

AN:

1112010

Other (OTH)

AF:

0.00588

AC:

355

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

265

531

796

1062

1327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0282

AC:

4299

AN:

152262

Hom.:

217

Cov.:

AF XY:

0.0270

AC XY:

2007

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0985

AC:

4091

AN:

41536

American (AMR)

AF:

0.00882

AC:

135

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68014

Other (OTH)

AF:

0.0213

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

193

386

579

772

965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0100

Hom.:

126

Bravo

AF:

0.0316

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0990

AC:

436

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00944

AC:

1146

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.46

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.082

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.029

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.24

REVEL

Benign

0.034

Sift

Benign

0.24

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.038

MVP

0.12

MPC

0.072

ClinPred

0.0029

GERP RS

-3.7

Varity_R

0.013

gMVP

0.072

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over