rs558770240

Positions:

• chr20-44160126-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020433.5(JPH2):​c.661T>C​(p.Phe221Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,502,424 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (6 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 6.24

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008279234).
• BP6: Variant 20-44160126-A-G is Benign according to our data. Variant chr20-44160126-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201798.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=7, Likely_benign=2}. Variant chr20-44160126-A-G is described in Lovd as [Benign]. Variant chr20-44160126-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00587 (890/151738) while in subpopulation AFR AF= 0.0208 (863/41522). AF 95% confidence interval is 0.0196. There are 10 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH2	NM_020433.5	c.661T>C	p.Phe221Leu	missense_variant	2/6	ENST00000372980.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH2	ENST00000372980.4	c.661T>C	p.Phe221Leu	missense_variant	2/6	5	NM_020433.5	P1

Frequencies

GnomAD3 genomes AF: 0.00588 AC: 891 AN: 151630 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

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: 0.0000590

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000751 AC: 77 AN: 102496 Hom.: 0 AF XY: 0.000610 AC XY: 35 AN XY: 57350

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000506

Gnomad OTH exome AF: 0.000625

GnomAD4 exome AF: 0.000560 AC: 757 AN: 1350686 Hom.: 6 Cov.: 32 AF XY: 0.000461 AC XY: 307 AN XY: 665360

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.000911

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000658

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000178

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00587 AC: 890 AN: 151738 Hom.: 10 Cov.: 32 AF XY: 0.00609 AC XY: 452 AN XY: 74168

Gnomad4 AFR AF: 0.0208

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00309 Hom.: 1

ExAC AF: 0.000781 AC: 18

Asia WGS AF: 0.000585 AC: 2 AN: 3432

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 22, 2015	p.Phe221Leu in exon 2 of JPH2: This variant is not expected to have clinical sig nificance due to high population frequency. It has been identified in 4.82% (8/ 166) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; rs558770240). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 19, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	JPH2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2022	See Variant Classification Assertion Criteria. -

Hypertrophic cardiomyopathy 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

JPH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2017

This alteration is classified as 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	Pathogenic	0.81
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.25
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.50
MutPred		0.39		Gain of helix (P = 0.0696);
MVP		0.76
ClinPred		0.082	T
GERP RS		2.0
Varity_R		0.33
gMVP		0.74

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: rs558770240; hg19: chr20-42788766;