chr20-44160163-G-C

Variant names:

• chr20-44160163-G-C
• rs398124358
• NM_020433.5:c.624C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_020433.5(JPH2):​c.624C>G​(p.Ala208Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,422,138 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A208A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: JPH2 NM_020433.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -0.460
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 20-44160163-G-C is Benign according to our data. Variant chr20-44160163-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95954.
• BP7: Synonymous conserved (PhyloP=-0.46 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 7 SD,AD,Unknown,AR gene

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.624C>G	p.Ala208Ala	synonymous	Exon 2 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.624C>G	p.Ala208Ala	synonymous	Exon 2 of 6	ENSP00000362071.3
	JPH2	ENST00000900331.1		c.624C>G	p.Ala208Ala	synonymous	Exon 2 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.687C>G	p.Ala229Ala	synonymous	Exon 3 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 151698 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00134 AC: 59 AN: 44172 AF XY: 0.00116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.000767

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000997 AC: 1266 AN: 1270332 Hom.: 7 Cov.: 32 AF XY: 0.000940 AC XY: 586 AN XY: 623194

African (AFR) AF: 0.0000826 AC: 2 AN: 24200

American (AMR) AF: 0.000181 AC: 3 AN: 16598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19310

East Asian (EAS) AF: 0.00 AC: 0 AN: 29150

South Asian (SAS) AF: 0.000531 AC: 34 AN: 63992

European-Finnish (FIN) AF: 0.0135 AC: 424 AN: 31342

Middle Eastern (MID) AF: 0.000269 AC: 1 AN: 3716

European-Non Finnish (NFE) AF: 0.000742 AC: 764 AN: 1029948

Other (OTH) AF: 0.000730 AC: 38 AN: 52076

GnomAD4 genome AF: 0.00157 AC: 239 AN: 151806 Hom.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 157 AN XY: 74206

African (AFR) AF: 0.0000722 AC: 3 AN: 41524

American (AMR) AF: 0.0000657 AC: 1 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.0151 AC: 158 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 67856

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000849 Hom.: 0

Bravo AF: 0.000450

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	4	not specified (4)
-	-	3	Hypertrophic cardiomyopathy 17 (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	JPH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.8
DANN	Benign	0.71
PhyloP100		-0.46
Mutation Taster		=100/0	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: rs398124358; hg19: chr20-42788803;