chr20-44160225-G-A

Variant names:

• chr20-44160225-G-A
• rs574746149
• NM_020433.5:c.562C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020433.5(JPH2):​c.562C>T​(p.Pro188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,483,740 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P188P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.84
• 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 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029876828).
• BP6: Variant 20-44160225-G-A is Benign according to our data. Variant chr20-44160225-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.562C>T	p.Pro188Ser	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.562C>T	p.Pro188Ser	missense	Exon 2 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.562C>T	p.Pro188Ser	missense	Exon 2 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.625C>T	p.Pro209Ser	missense	Exon 3 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 302 AN: 151954 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000418 AC: 38 AN: 90832 AF XY: 0.000297

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000650

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000282

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.000184 AC: 245 AN: 1331678 Hom.: 3 Cov.: 32 AF XY: 0.000162 AC XY: 106 AN XY: 653742

African (AFR) AF: 0.00658 AC: 179 AN: 27210

American (AMR) AF: 0.00100 AC: 30 AN: 29946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22444

East Asian (EAS) AF: 0.00 AC: 0 AN: 32130

South Asian (SAS) AF: 0.0000139 AC: 1 AN: 72014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33190

Middle Eastern (MID) AF: 0.000236 AC: 1 AN: 4234

European-Non Finnish (NFE) AF: 0.00000853 AC: 9 AN: 1055110

Other (OTH) AF: 0.000451 AC: 25 AN: 55400

GnomAD4 genome AF: 0.00201 AC: 305 AN: 152062 Hom.: 1 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74336

African (AFR) AF: 0.00688 AC: 286 AN: 41548

American (AMR) AF: 0.000983 AC: 15 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10526

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.00225

ExAC AF: 0.0000941 AC: 4

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N
PhyloP100		1.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	0.79	T
Polyphen		0.15	B
Vest4		0.15
MVP		0.71
ClinPred		0.0082	T
GERP RS		2.3
Varity_R		0.049
gMVP		0.23
Mutation Taster		=95/5	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: rs574746149; hg19: chr20-42788865;