rs144022614

Positions:

• chr20-44159931-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020433.5(JPH2):​c.856A>G​(p.Thr286Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,560,836 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00097 (4 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.58

Genes affected

JPH2 (HGNC:14202): (junctophilin 2) 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. Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0151696205).
• BP6: Variant 20-44159931-T-C is Benign according to our data. Variant chr20-44159931-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 201799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-44159931-T-C is described in Lovd as [Benign]. Variant chr20-44159931-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (175/102542) while in subpopulation NFE AF= 0.00231 (108/46852). AF 95% confidence interval is 0.00195. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH2	NM_020433.5	c.856A>G	p.Thr286Ala	missense_variant	2/6	ENST00000372980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4	c.856A>G	p.Thr286Ala	missense_variant	2/6	5	NM_020433.5	P1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 175 AN: 102428 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.000830

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00671

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00230

Gnomad OTH AF: 0.000787

GnomAD3 exomes AF: 0.000997 AC: 243 AN: 243780 Hom.: 1 AF XY: 0.00105 AC XY: 139 AN XY: 131970

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000404

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00358

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000970 AC: 1414 AN: 1458294 Hom.: 4 Cov.: 33 AF XY: 0.000924 AC XY: 670 AN XY: 725220

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00375

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000995

GnomAD4 genome AF: 0.00171 AC: 175 AN: 102542 Hom.: 0 Cov.: 30 AF XY: 0.00188 AC XY: 95 AN XY: 50496

Gnomad4 AFR AF: 0.000272

Gnomad4 AMR AF: 0.000190

Gnomad4 ASJ AF: 0.000830

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00671

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.000779

Alfa AF: 0.000737 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.000981

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2015	p.Thr286Ala in exon 2 of JPH2: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (27/5220) of Finnish chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs144022614). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2023	- -

Supraventricular tachycardia;C0878544:Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 01, 2019

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 06, 2022

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2018

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	0.30
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Polyphen		0.92	P
Vest4		0.56
MVP		0.87
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.60
gMVP		0.47

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

Other links and lift over

dbSNP: rs144022614; hg19: chr20-42788571; COSMIC: COSV65904624;