NM_020647.4:c.1140-4368T>C

Variant names:

• chr8-74263871-A-G
• rs10504566
• NM_020647.4:c.1140-4368T>C

Variant summary

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

The NM_020647.4(JPH1):​c.1140-4368T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0702 in 152,198 control chromosomes in the GnomAD database, including 957 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 0.070 (957 hom., cov: 32)
• Consequence: JPH1 NM_020647.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.618
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 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.1140-4368T>C		intron	N/A	NP_065698.1
	JPH1	NM_001317830.2		c.1140-4368T>C		intron	N/A	NP_001304759.1
	JPH1	NM_001363050.1		c.1140-4368T>C		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.1140-4368T>C		intron	N/A	ENSP00000344488.4
	JPH1	ENST00000519947.1	TSL:1	n.*535-4368T>C		intron	N/A	ENSP00000429652.1

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10645 AN: 152080 Hom.: 950 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.0847

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00800

Gnomad OTH AF: 0.0621

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

GnomAD4 genome AF: 0.0702 AC: 10690 AN: 152198 Hom.: 957 Cov.: 32 AF XY: 0.0689 AC XY: 5125 AN XY: 74422

African (AFR) AF: 0.203 AC: 8435 AN: 41462

American (AMR) AF: 0.0354 AC: 542 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3472

East Asian (EAS) AF: 0.0849 AC: 440 AN: 5182

South Asian (SAS) AF: 0.0539 AC: 260 AN: 4824

European-Finnish (FIN) AF: 0.00989 AC: 105 AN: 10622

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.00800 AC: 544 AN: 68024

Other (OTH) AF: 0.0629 AC: 133 AN: 2116

Alfa AF: 0.0184 Hom.: 27

Bravo AF: 0.0783

Asia WGS AF: 0.104 AC: 360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.62
Mutation Taster		=92/8	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: rs10504566; hg19: chr8-75176106;