20-44115947-G-C

Variant names:

• chr20-44115947-G-C
• rs74352869
• NM_020433.5:c.1728C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020433.5(JPH2):​c.1728C>G​(p.Pro576Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 1,567,210 control chromosomes in the GnomAD database, including 38,820 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3786 hom., cov: 32)
  • Exomes 𝑓: 0.22 (35034 hom.)
• Consequence: JPH2 NM_020433.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.416
• Publications: 12 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, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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
• dilated cardiomyopathy

  Inheritance: SD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-44115947-G-C is Benign according to our data. Variant chr20-44115947-G-C is described in ClinVar as Benign. ClinVar VariationId is 137609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.416 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	NM_020433.5	MANE Select	c.1728C>G	p.Pro576Pro	synonymous	Exon 4 of 6	NP_065166.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.1728C>G	p.Pro576Pro	synonymous	Exon 4 of 6	ENSP00000362071.3
	JPH2	ENST00000900331.1		c.1809C>G	p.Pro603Pro	synonymous	Exon 5 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.1791C>G	p.Pro597Pro	synonymous	Exon 5 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32982 AN: 151938 Hom.: 3774 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.0827

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.170 AC: 29150 AN: 171214 AF XY: 0.168

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.0644

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.215 AC: 304879 AN: 1415164 Hom.: 35034 Cov.: 37 AF XY: 0.211 AC XY: 148255 AN XY: 701612

African (AFR) AF: 0.255 AC: 8374 AN: 32798

American (AMR) AF: 0.112 AC: 4441 AN: 39722

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 5950 AN: 25496

East Asian (EAS) AF: 0.0477 AC: 1825 AN: 38260

South Asian (SAS) AF: 0.0839 AC: 6984 AN: 83206

European-Finnish (FIN) AF: 0.221 AC: 7950 AN: 35912

Middle Eastern (MID) AF: 0.159 AC: 872 AN: 5474

European-Non Finnish (NFE) AF: 0.234 AC: 256395 AN: 1095356

Other (OTH) AF: 0.205 AC: 12088 AN: 58940

GnomAD4 genome AF: 0.217 AC: 33025 AN: 152046 Hom.: 3786 Cov.: 32 AF XY: 0.212 AC XY: 15785 AN XY: 74324

African (AFR) AF: 0.256 AC: 10619 AN: 41458

American (AMR) AF: 0.150 AC: 2298 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 817 AN: 3470

East Asian (EAS) AF: 0.0677 AC: 349 AN: 5156

South Asian (SAS) AF: 0.0828 AC: 399 AN: 4820

European-Finnish (FIN) AF: 0.216 AC: 2289 AN: 10594

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.228 AC: 15504 AN: 67934

Other (OTH) AF: 0.197 AC: 416 AN: 2114

Alfa AF: 0.221 Hom.: 712

Bravo AF: 0.215

Asia WGS AF: 0.0860 AC: 298 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Hypertrophic cardiomyopathy 17 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.96
DANN	Benign	0.55
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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: rs74352869; hg19: chr20-42744587; COSMIC: COSV65902448;