chr20-44116256-G-C

Variant names:

• chr20-44116256-G-C
• rs1471827464
• NM_020433.5:c.1419C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020433.5(JPH2):​c.1419C>G​(p.His473Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,362,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H473Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134
• 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: 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30847058).

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.1419C>G	p.His473Gln	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.1419C>G	p.His473Gln	missense	Exon 4 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.1500C>G	p.His500Gln	missense	Exon 5 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.1482C>G	p.His494Gln	missense	Exon 5 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000897 AC: 1 AN: 111510 AF XY: 0.0000163

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000249

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 14 AN: 1362710 Hom.: 0 Cov.: 34 AF XY: 0.0000119 AC XY: 8 AN XY: 671552

African (AFR) AF: 0.00 AC: 0 AN: 29432

American (AMR) AF: 0.00 AC: 0 AN: 33204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23754

East Asian (EAS) AF: 0.00 AC: 0 AN: 33960

South Asian (SAS) AF: 0.00 AC: 0 AN: 76170

European-Finnish (FIN) AF: 0.0000273 AC: 1 AN: 36676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4036

European-Non Finnish (NFE) AF: 0.0000122 AC: 13 AN: 1068810

Other (OTH) AF: 0.00 AC: 0 AN: 56668

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.13
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.11	T
Sift4G	Benign	0.14	T
Polyphen		0.99	D
Vest4		0.21
MutPred		0.21		Loss of glycosylation at T477 (P = 0.1663)
MVP		0.82
ClinPred		0.53	D
GERP RS		-0.53
Varity_R		0.097
gMVP		0.56
Mutation Taster		=51/49	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: rs1471827464; hg19: chr20-42744896;