NM_020433.5:c.1179C>T

Variant names:

• chr20-44118614-G-A
• rs7268512
• NM_020433.5:c.1179C>T

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.1179C>T​(p.His393His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0884 in 1,608,650 control chromosomes in the GnomAD database, including 6,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (563 hom., cov: 33)
  • Exomes 𝑓: 0.089 (6385 hom.)
• Consequence: JPH2 NM_020433.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0590
• Publications: 8 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 20-44118614-G-A is Benign according to our data. Variant chr20-44118614-G-A is described in ClinVar as Benign. ClinVar VariationId is 137606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.059 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0994 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	NM_020433.5	MANE Select	c.1179C>T	p.His393His	synonymous	Exon 3 of 6	NP_065166.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.1179C>T	p.His393His	synonymous	Exon 3 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.1260C>T	p.His420His	synonymous	Exon 4 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.1242C>T	p.His414His	synonymous	Exon 4 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12519 AN: 152162 Hom.: 563 Cov.: 33

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0558

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0745

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0822

GnomAD2 exomes AF: 0.0688 AC: 17051 AN: 247884 AF XY: 0.0685

Gnomad AFR exome AF: 0.0782

Gnomad AMR exome AF: 0.0424

Gnomad ASJ exome AF: 0.0551

Gnomad EAS exome AF: 0.00861

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.0949

Gnomad OTH exome AF: 0.0790

GnomAD4 exome AF: 0.0890 AC: 129683 AN: 1456370 Hom.: 6385 Cov.: 32 AF XY: 0.0875 AC XY: 63385 AN XY: 724738

African (AFR) AF: 0.0774 AC: 2589 AN: 33444

American (AMR) AF: 0.0432 AC: 1931 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0564 AC: 1473 AN: 26132

East Asian (EAS) AF: 0.00499 AC: 198 AN: 39694

South Asian (SAS) AF: 0.0299 AC: 2579 AN: 86248

European-Finnish (FIN) AF: 0.0766 AC: 3771 AN: 49226

Middle Eastern (MID) AF: 0.0627 AC: 361 AN: 5762

European-Non Finnish (NFE) AF: 0.101 AC: 111882 AN: 1110818

Other (OTH) AF: 0.0812 AC: 4899 AN: 60324

GnomAD4 genome AF: 0.0822 AC: 12515 AN: 152280 Hom.: 563 Cov.: 33 AF XY: 0.0797 AC XY: 5938 AN XY: 74470

African (AFR) AF: 0.0793 AC: 3296 AN: 41546

American (AMR) AF: 0.0556 AC: 851 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3470

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5190

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4830

European-Finnish (FIN) AF: 0.0745 AC: 790 AN: 10610

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6894 AN: 68010

Other (OTH) AF: 0.0814 AC: 172 AN: 2114

Alfa AF: 0.0885 Hom.: 191

Bravo AF: 0.0811

Asia WGS AF: 0.0240 AC: 84 AN: 3478

EpiCase AF: 0.0951

EpiControl AF: 0.0917

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 17 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.2
DANN	Benign	0.69
PhyloP100		0.059
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: rs7268512; hg19: chr20-42747254;