rs6093935

Variant names:

• chr20-44114814-A-G
• rs6093935
• NM_020433.5:c.2073T>C

Your query was ambiguous. Multiple possible variants found:

• chr20-44114814-A-G
• chr20-44114814-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020433.5(JPH2):​c.2073T>C​(p.Phe691Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,604,238 control chromosomes in the GnomAD database, including 75,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8569 hom., cov: 30)
  • Exomes 𝑓: 0.29 (66512 hom.)
• Consequence: JPH2 NM_020433.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.322
• Publications: 19 publications found

Genes affected

JPH2 (HGNC:14202): (junctophilin 2) 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. Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described. [provided by RefSeq, Jul 2008]

JPH2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: SD, AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen
• cardiomyopathy, dilated, 2E

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 20-44114814-A-G is Benign according to our data. Variant chr20-44114814-A-G is described in ClinVar as Benign. ClinVar VariationId is 137611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.322 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020433.5. 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
	JPH2	NM_020433.5	MANE Select	c.2073T>C	p.Phe691Phe	synonymous	Exon 5 of 6	NP_065166.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.2073T>C	p.Phe691Phe	synonymous	Exon 5 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.2154T>C	p.Phe718Phe	synonymous	Exon 6 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.2136T>C	p.Phe712Phe	synonymous	Exon 6 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49063 AN: 151558 Hom.: 8541 Cov.: 30

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.0921

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.316

GnomAD2 exomes AF: 0.248 AC: 58346 AN: 235182 AF XY: 0.242

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.0877

Gnomad FIN exome AF: 0.280

Gnomad NFE exome AF: 0.297

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.293 AC: 426299 AN: 1452562 Hom.: 66512 Cov.: 35 AF XY: 0.288 AC XY: 207531 AN XY: 721336

African (AFR) AF: 0.459 AC: 15342 AN: 33414

American (AMR) AF: 0.159 AC: 6919 AN: 43456

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 8369 AN: 25814

East Asian (EAS) AF: 0.0705 AC: 2783 AN: 39480

South Asian (SAS) AF: 0.124 AC: 10381 AN: 83998

European-Finnish (FIN) AF: 0.284 AC: 14981 AN: 52708

Middle Eastern (MID) AF: 0.222 AC: 1272 AN: 5742

European-Non Finnish (NFE) AF: 0.315 AC: 348681 AN: 1107848

Other (OTH) AF: 0.292 AC: 17571 AN: 60102

GnomAD4 genome AF: 0.324 AC: 49133 AN: 151676 Hom.: 8569 Cov.: 30 AF XY: 0.316 AC XY: 23400 AN XY: 74126

African (AFR) AF: 0.458 AC: 18919 AN: 41308

American (AMR) AF: 0.219 AC: 3337 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1127 AN: 3466

East Asian (EAS) AF: 0.0917 AC: 472 AN: 5148

South Asian (SAS) AF: 0.117 AC: 560 AN: 4784

European-Finnish (FIN) AF: 0.281 AC: 2954 AN: 10528

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.305 AC: 20682 AN: 67876

Other (OTH) AF: 0.311 AC: 655 AN: 2104

Alfa AF: 0.306 Hom.: 11281

Bravo AF: 0.327

Asia WGS AF: 0.130 AC: 454 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 17 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.9
DANN	Benign	0.68
PhyloP100		0.32
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: rs6093935; hg19: chr20-42743454; COSMIC: COSV65902426;