8-74244914-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020647.4(JPH1):c.1520C>T(p.Thr507Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,112 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: JPH1 NM_020647.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.190

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038918555).
• BP6: Variant 8-74244914-G-A is Benign according to our data. Variant chr8-74244914-G-A is described in ClinVar as [Benign]. Clinvar id is 3033657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 433 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH1	NM_020647.4	c.1520C>T	p.Thr507Met	missense_variant	4/6	ENST00000342232.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH1	ENST00000342232.5	c.1520C>T	p.Thr507Met	missense_variant	4/6	1	NM_020647.4	P1
JPH1	ENST00000519947.1	c.*915C>T		3_prime_UTR_variant, NMD_transcript_variant	4/5	1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 433 AN: 152112 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00171 AC: 431 AN: 251412 Hom.: 1 AF XY: 0.00147 AC XY: 200 AN XY: 135874

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00140 AC: 2049 AN: 1461882 Hom.: 5 Cov.: 32 AF XY: 0.00135 AC XY: 983 AN XY: 727240

Gnomad4 AFR exome AF: 0.00783

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00419

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152230 Hom.: 1 Cov.: 31 AF XY: 0.00277 AC XY: 206 AN XY: 74436

Gnomad4 AFR AF: 0.00725

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00300

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00185 AC: 225

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

JPH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	8.0
Dann	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.071
Sift	Benign	0.073	T
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.17
MPC		0.096
ClinPred		0.0020	T
GERP RS		-2.2
Varity_R		0.015
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs16938829; hg19: chr8-75157149; COSMIC: COSV60610183; COSMIC: COSV60610183;