chr8-74244540-C-G

Variant names:

• chr8-74244540-C-G
• rs75912309
• NM_020647.4:c.1894G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020647.4(JPH1):​c.1894G>C​(p.Glu632Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JPH1 NM_020647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37151456).

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.1894G>C	p.Glu632Gln	missense	Exon 4 of 6	NP_065698.1	Q9HDC5
	JPH1	NM_001317830.2		c.1894G>C	p.Glu632Gln	missense	Exon 4 of 6	NP_001304759.1	Q9HDC5
	JPH1	NM_001363050.1		c.1894G>C	p.Glu632Gln	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.1894G>C	p.Glu632Gln	missense	Exon 4 of 6	ENSP00000344488.4	Q9HDC5
	JPH1	ENST00000519947.1	TSL:1	n.*1289G>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000429652.1	E5RHU9
	JPH1	ENST00000519947.1	TSL:1	n.*1289G>C		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: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.0
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Uncertain	0.018	D
Sift4G	Benign	0.12	T
Polyphen		0.94	P
Vest4		0.47
MutPred		0.36		Gain of catalytic residue at E632 (P = 0.0558)
MVP		0.48
MPC		0.11
ClinPred		0.60	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.49
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

Other links and lift over

dbSNP: rs75912309; hg19: chr8-75156775;