8-74249884-T-C

Variant names:

• chr8-74249884-T-C
• rs10504563
• NM_020647.4:c.1259-4709A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020647.4(JPH1):​c.1259-4709A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0517 in 152,226 control chromosomes in the GnomAD database, including 646 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.052 (646 hom., cov: 33)
• Consequence: JPH1 NM_020647.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH1	NM_020647.4	MANE Select	c.1259-4709A>G		intron	N/A	NP_065698.1
	JPH1	NM_001317830.2		c.1259-4709A>G		intron	N/A	NP_001304759.1
	JPH1	NM_001363050.1		c.1259-4709A>G		intron	N/A	NP_001349979.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH1	ENST00000342232.5	TSL:1 MANE Select	c.1259-4709A>G		intron	N/A	ENSP00000344488.4
	JPH1	ENST00000519947.1	TSL:1	n.*654-4709A>G		intron	N/A	ENSP00000429652.1

Frequencies

GnomAD3 genomes AF: 0.0516 AC: 7853 AN: 152108 Hom.: 645 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.0446

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0517 AC: 7869 AN: 152226 Hom.: 646 Cov.: 33 AF XY: 0.0500 AC XY: 3723 AN XY: 74440

African (AFR) AF: 0.173 AC: 7201 AN: 41516

American (AMR) AF: 0.0180 AC: 276 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 159 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00174 AC: 118 AN: 68010

Other (OTH) AF: 0.0441 AC: 93 AN: 2108

Alfa AF: 0.0390 Hom.: 80

Bravo AF: 0.0579

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.35
DANN	Benign	0.31
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs10504563; hg19: chr8-75162119;