NM_020433.5:c.661T>C

Variant names:

• chr20-44160126-A-G
• rs558770240
• NM_020433.5:c.661T>C

Variant summary

Our verdict is Benign. The variant received -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:2 B:9
• Conservation: PhyloP100: 6.24
• Publications: 5 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 -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 VariationId is 201798.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 Unknown,SD,AR,AD 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.661T>C	p.Phe221Leu	missense	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.661T>C	p.Phe221Leu	missense	Exon 2 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.661T>C	p.Phe221Leu	missense	Exon 2 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.724T>C	p.Phe242Leu	missense	Exon 3 of 7	ENSP00000620266.1

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

GnomAD2 exomes AF: 0.000751 AC: 77 AN: 102496 AF XY: 0.000610

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 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

African (AFR) AF: 0.0216 AC: 611 AN: 28230

American (AMR) AF: 0.000911 AC: 29 AN: 31816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23646

East Asian (EAS) AF: 0.00 AC: 0 AN: 33188

South Asian (SAS) AF: 0.0000658 AC: 5 AN: 75936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33194

Middle Eastern (MID) AF: 0.00119 AC: 5 AN: 4214

European-Non Finnish (NFE) AF: 0.0000178 AC: 19 AN: 1064434

Other (OTH) AF: 0.00157 AC: 88 AN: 56028

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

African (AFR) AF: 0.0208 AC: 863 AN: 41522

American (AMR) AF: 0.00125 AC: 19 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67810

Other (OTH) AF: 0.00190 AC: 4 AN: 2102

Alfa AF: 0.00309 Hom.: 1

ExAC AF: 0.000781 AC: 18

Asia WGS AF: 0.000585 AC: 2 AN: 3432

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	1	Hypertrophic cardiomyopathy (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy 17 (1)
-	-	1	JPH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.2
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
Mutation Taster		=75/25	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: rs558770240; hg19: chr20-42788766;