chr8-74244702-A-G

Position:

• chr8-74244702-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020647.4(JPH1):​c.1732T>C​(p.Ser578Pro) 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. 15/21 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: JPH1 NM_020647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1816122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH1	NM_020647.4	c.1732T>C	p.Ser578Pro	missense_variant	4/6	ENST00000342232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH1	ENST00000342232.5	c.1732T>C	p.Ser578Pro	missense_variant	4/6	1	NM_020647.4	P1
JPH1	ENST00000519947.1	c.*1127T>C		3_prime_UTR_variant, NMD_transcript_variant	4/5	1
JPH1	ENST00000518195.1	n.87T>C		non_coding_transcript_exon_variant	1/3	4

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

May 30, 2023

The c.1732T>C (p.S578P) alteration is located in exon 4 (coding exon 4) of the JPH1 gene. This alteration results from a T to C substitution at nucleotide position 1732, causing the serine (S) at amino acid position 578 to be replaced by a proline (P). 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	0.066
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.13
Sift	Benign	0.21	T
Sift4G	Benign	0.39	T
Polyphen		0.64	P
Vest4		0.40
MutPred		0.13		Loss of phosphorylation at S578 (P = 0.0298);
MVP		0.50
MPC		0.26
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.11
gMVP		0.33

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: chr8-75156937;