20-44115738-G-C

Variant names:

• chr20-44115738-G-C
• rs1600828763
• NM_020433.5:c.1937C>G
• JPH2 p.Thr646Ser

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020433.5(JPH2):​c.1937C>G​(p.Thr646Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T646A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.771
• Publications: 0 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: AR, SD, 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053353816).

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.1937C>G	p.Thr646Ser	missense	Exon 4 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.1937C>G	p.Thr646Ser	missense	Exon 4 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.2018C>G	p.Thr673Ser	missense	Exon 5 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.2000C>G	p.Thr667Ser	missense	Exon 5 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461100 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 726952

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 17;C5561970:Cardiomyopathy, dilated, 2E (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.77
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.77
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.050
Sift	Benign	0.62	T
Sift4G	Benign	0.80	T
Varity_R		0.036
gMVP		0.12
Mutation Taster		=88/12	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1600828763; hg19: chr20-42744378;