20-44186648-C-T

Variant names:

• chr20-44186648-C-T
• rs988100071
• NM_020433.5:c.58G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_020433.5(JPH2):​c.58G>A​(p.Gly20Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.73
• Publications: 1 publications found

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]

JPH2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: SD, AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen
• cardiomyopathy, dilated, 2E

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20660216).
• BP6: Variant 20-44186648-C-T is Benign according to our data. Variant chr20-44186648-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 520525.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	NM_020433.5	MANE Select	c.58G>A	p.Gly20Arg	missense	Exon 1 of 6	NP_065166.2
	JPH2	NM_175913.4		c.58G>A	p.Gly20Arg	missense	Exon 1 of 2	NP_787109.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.58G>A	p.Gly20Arg	missense	Exon 1 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000342272.3	TSL:1	c.58G>A	p.Gly20Arg	missense	Exon 1 of 2	ENSP00000344590.3	Q9BR39-2
	JPH2	ENST00000900331.1		c.58G>A	p.Gly20Arg	missense	Exon 1 of 7	ENSP00000570390.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456292 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 724736

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111702

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.079
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.30
MutPred		0.34		Gain of sheet (P = 0.0221)
MVP		0.77
ClinPred		0.96	D
GERP RS		3.6
PromoterAI		0.011	Neutral
Varity_R		0.23
gMVP		0.39
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs988100071; hg19: chr20-42815288;