8-74244859-C-T

Variant names:

• chr8-74244859-C-T
• rs140054578
• NM_020647.4:c.1575G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_020647.4(JPH1):​c.1575G>A​(p.Ala525Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,174 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: JPH1 NM_020647.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 8-74244859-C-T is Benign according to our data. Variant chr8-74244859-C-T is described in ClinVar as Benign. ClinVar VariationId is 789520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH1	NM_020647.4	MANE Select	c.1575G>A	p.Ala525Ala	synonymous	Exon 4 of 6	NP_065698.1	Q9HDC5
	JPH1	NM_001317830.2		c.1575G>A	p.Ala525Ala	synonymous	Exon 4 of 6	NP_001304759.1	Q9HDC5
	JPH1	NM_001363050.1		c.1575G>A	p.Ala525Ala	synonymous	Exon 4 of 6	NP_001349979.1	Q9HDC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH1	ENST00000342232.5	TSL:1 MANE Select	c.1575G>A	p.Ala525Ala	synonymous	Exon 4 of 6	ENSP00000344488.4	Q9HDC5
	JPH1	ENST00000519947.1	TSL:1	n.*970G>A		non_coding_transcript_exon	Exon 4 of 5	ENSP00000429652.1	E5RHU9
	JPH1	ENST00000519947.1	TSL:1	n.*970G>A		3_prime_UTR	Exon 4 of 5	ENSP00000429652.1	E5RHU9

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152166 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00205 AC: 515 AN: 251454 AF XY: 0.00199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00115 AC: 1679 AN: 1461892 Hom.: 24 Cov.: 32 AF XY: 0.00123 AC XY: 895 AN XY: 727248

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 1117 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000282 AC: 314 AN: 1112012

Other (OTH) AF: 0.00290 AC: 175 AN: 60396

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152282 Hom.: 5 Cov.: 31 AF XY: 0.00121 AC XY: 90 AN XY: 74452

African (AFR) AF: 0.000168 AC: 7 AN: 41548

American (AMR) AF: 0.000392 AC: 6 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0421 AC: 146 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68032

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00358 Hom.: 3

Bravo AF: 0.00140

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.1
DANN	Benign	0.45
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs140054578; hg19: chr8-75157094;