rs796219248

Variant names:

• chr20-44160139-C-T
• rs796219248
• NM_020433.5:c.648G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_020433.5(JPH2):​c.648G>A​(p.Lys216Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000339 in 1,450,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: JPH2 NM_020433.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.63
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 20-44160139-C-T is Benign according to our data. Variant chr20-44160139-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 264069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.

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.648G>A	p.Lys216Lys	synonymous	Exon 2 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.648G>A	p.Lys216Lys	synonymous	Exon 2 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.648G>A	p.Lys216Lys	synonymous	Exon 2 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.711G>A	p.Lys237Lys	synonymous	Exon 3 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.000264 AC: 40 AN: 151652 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000531

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 11 AN: 65878 AF XY: 0.0000784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000400

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000347 AC: 451 AN: 1298516 Hom.: 0 Cov.: 32 AF XY: 0.000334 AC XY: 213 AN XY: 638544

African (AFR) AF: 0.000120 AC: 3 AN: 25022

American (AMR) AF: 0.0000482 AC: 1 AN: 20760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21208

East Asian (EAS) AF: 0.00 AC: 0 AN: 30106

South Asian (SAS) AF: 0.00 AC: 0 AN: 68794

European-Finnish (FIN) AF: 0.0000310 AC: 1 AN: 32264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3902

European-Non Finnish (NFE) AF: 0.000414 AC: 432 AN: 1043026

Other (OTH) AF: 0.000262 AC: 14 AN: 53434

GnomAD4 genome AF: 0.000264 AC: 40 AN: 151652 Hom.: 0 Cov.: 32 AF XY: 0.000270 AC XY: 20 AN XY: 74066

African (AFR) AF: 0.0000966 AC: 4 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000531 AC: 36 AN: 67842

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000529 Hom.: 0

Bravo AF: 0.000230

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Hypertrophic cardiomyopathy 17 (3)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.8
DANN	Benign	0.52
PhyloP100		2.6
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: rs796219248; hg19: chr20-42788779;