14-23570984-C-G

Position:

• chr14-23570984-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001146028.2(JPH4):​c.1747G>C​(p.Gly583Arg) 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. 14/21 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: JPH4 NM_001146028.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0390

Genes affected

JPH4 (HGNC:20156): (junctophilin 4) This gene encodes a member of the junctophilin family of transmembrane proteins that are involved in the formation of the junctional membrane complexes between the plasma membrane and the endoplasmic/sarcoplasmic reticulum in excitable cells. The encoded protein contains a conserved N-terminal repeat region called the membrane occupation and recognition nexus sequence that is found in other members of the junctophilin family. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04809758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JPH4	NM_001146028.2	c.1747G>C	p.Gly583Arg	missense_variant	5/6	ENST00000356300.9	NP_001139500.1
JPH4	NM_032452.3	c.1747G>C	p.Gly583Arg	missense_variant	6/7		NP_115828.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JPH4	ENST00000356300.9	c.1747G>C	p.Gly583Arg	missense_variant	5/6	1	NM_001146028.2	ENSP00000348648	P1
JPH4	ENST00000397118.7	c.1747G>C	p.Gly583Arg	missense_variant	6/7	1		ENSP00000380307	P1
JPH4	ENST00000544177.1	c.742G>C	p.Gly248Arg	missense_variant	3/4	2		ENSP00000439562

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.1747G>C (p.G583R) alteration is located in exon 6 (coding exon 4) of the JPH4 gene. This alteration results from a G to C substitution at nucleotide position 1747, causing the glycine (G) at amino acid position 583 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.048	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	.;N;N;.
MutationTaster	Benign	0.50	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.62	.;N;N;D
REVEL	Benign	0.065
Sift	Benign	0.81	.;T;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.053, 0.25	.;B;B;B
Vest4		0.26
MutPred		0.10		.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;
MVP		0.18
MPC		0.18
ClinPred		0.13	T
GERP RS		2.6
Varity_R		0.054
gMVP		0.29

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24040193;