chr8-74245112-T-C

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.1322A>G(p.Lys441Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00318 in 1,613,026 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 69 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 64 hom. )

Consequence

JPH1
NM_020647.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.38

Publications

7 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=0.0018860102).

BP6

Variant 8-74245112-T-C is Benign according to our data. Variant chr8-74245112-T-C is described in ClinVar as Benign. ClinVar VariationId is 768246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH1	NM_020647.4 link	c.1322A>G	p.Lys441Arg	missense_variant	Exon 4 of 6	ENST00000342232.5	NP_065698.1	Q9HDC5Q86VR1Q7Z682

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JPH1	ENST00000342232.5 link	c.1322A>G	p.Lys441Arg	missense_variant	Exon 4 of 6	1	NM_020647.4	ENSP00000344488.4	Q9HDC5
JPH1	ENST00000519947.1 link	n.*717A>G		non_coding_transcript_exon_variant	Exon 4 of 5	1		ENSP00000429652.1	E5RHU9
JPH1	ENST00000519947.1 link	n.*717A>G		3_prime_UTR_variant	Exon 4 of 5	1		ENSP00000429652.1	E5RHU9

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2426

AN:

151666

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0524

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.00209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0111

GnomAD2 exomes

AF:

0.00459

AC:

1151

AN:

250564

AF XY:

0.00362

show subpopulations

Gnomad AFR exome

AF:

0.0548

Gnomad AMR exome

AF:

0.00418

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00185

AC:

2708

AN:

1461246

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1213

AN XY:

726954

show subpopulations

African (AFR)

AF:

0.0559

AC:

1864

AN:

33360

American (AMR)

AF:

0.00449

AC:

200

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.00192

AC:

165

AN:

86110

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000172

AC:

191

AN:

1111852

Other (OTH)

AF:

0.00437

AC:

264

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

138

276

414

552

690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.0160

AC:

2429

AN:

151780

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1167

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.0523

AC:

2157

AN:

41262

American (AMR)

AF:

0.0138

AC:

210

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000775

AC:

AN:

5162

South Asian (SAS)

AF:

0.00209

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67974

Other (OTH)

AF:

0.0109

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00656

Hom.:

Bravo

AF:

0.0198

ESP6500AA

AF:

0.0470

AC:

207

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00541

AC:

657

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

4.4

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.70

REVEL

Benign

0.092

Sift

Benign

0.37

Sift4G

Benign

0.52

Polyphen

0.027

Vest4

0.28

MVP

0.35

MPC

0.16

ClinPred

0.013

GERP RS

3.0

Varity_R

0.070

gMVP

0.17

Mutation Taster

=78/22

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over