8-74244830-C-A

Variant names:

• chr8-74244830-C-A
• rs142421841
• NM_020647.4:c.1604G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020647.4(JPH1):​c.1604G>T​(p.Arg535Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. R535C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JPH1 NM_020647.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.745
• Publications: 2 publications found

Genes affected

JPH1 (HGNC:14201): (junctophilin 1) 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. [provided by RefSeq, Jul 2008]

JPH1 Gene-Disease associations (from GenCC):

• congenital myopathy 25

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09590897).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020647.4. 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
	JPH1	NM_020647.4	MANE Select	c.1604G>T	p.Arg535Leu	missense	Exon 4 of 6	NP_065698.1	Q9HDC5
	JPH1	NM_001317830.2		c.1604G>T	p.Arg535Leu	missense	Exon 4 of 6	NP_001304759.1	Q9HDC5
	JPH1	NM_001363050.1		c.1604G>T	p.Arg535Leu	missense	Exon 4 of 6	NP_001349979.1	Q9HDC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH1	ENST00000342232.5	TSL:1 MANE Select	c.1604G>T	p.Arg535Leu	missense	Exon 4 of 6	ENSP00000344488.4	Q9HDC5
	JPH1	ENST00000519947.1	TSL:1	n.*999G>T		non_coding_transcript_exon	Exon 4 of 5	ENSP00000429652.1	E5RHU9
	JPH1	ENST00000519947.1	TSL:1	n.*999G>T		3_prime_UTR	Exon 4 of 5	ENSP00000429652.1	E5RHU9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.74
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.027
Sift	Benign	0.59	T
Sift4G	Benign	0.35	T
Polyphen		0.072	B
Vest4		0.38
MutPred		0.44		Gain of ubiquitination at K531 (P = 0.0566)
MVP		0.27
MPC		0.13
ClinPred		0.29	T
GERP RS		1.3
Varity_R		0.076
gMVP		0.28
Mutation Taster		=83/17	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: rs142421841; hg19: chr8-75157065;