rs144022614

Variant names:

• chr20-44159931-T-C
• rs144022614
• NM_020433.5:c.856A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020433.5(JPH2):​c.856A>G​(p.Thr286Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,560,836 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00097 (4 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.58
• Publications: 8 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, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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
• dilated cardiomyopathy

  Inheritance: SD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0151696205).
• BP6: Variant 20-44159931-T-C is Benign according to our data. Variant chr20-44159931-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 201799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD,AD,Unknown,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	NM_020433.5	MANE Select	c.856A>G	p.Thr286Ala	missense	Exon 2 of 6	NP_065166.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.856A>G	p.Thr286Ala	missense	Exon 2 of 6	ENSP00000362071.3

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 175 AN: 102428 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.000830

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00671

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00230

Gnomad OTH AF: 0.000787

GnomAD2 exomes AF: 0.000997 AC: 243 AN: 243780 AF XY: 0.00105

Gnomad AFR exome AF: 0.000192

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000404

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00358

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000970 AC: 1414 AN: 1458294 Hom.: 4 Cov.: 33 AF XY: 0.000924 AC XY: 670 AN XY: 725220

African (AFR) AF: 0.000179 AC: 6 AN: 33438

American (AMR) AF: 0.000180 AC: 8 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26006

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 85570

European-Finnish (FIN) AF: 0.00375 AC: 194 AN: 51780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00103 AC: 1140 AN: 1111226

Other (OTH) AF: 0.000995 AC: 60 AN: 60320

GnomAD4 genome AF: 0.00171 AC: 175 AN: 102542 Hom.: 0 Cov.: 30 AF XY: 0.00188 AC XY: 95 AN XY: 50496

African (AFR) AF: 0.000272 AC: 7 AN: 25766

American (AMR) AF: 0.000190 AC: 2 AN: 10546

Ashkenazi Jewish (ASJ) AF: 0.000830 AC: 2 AN: 2410

East Asian (EAS) AF: 0.00 AC: 0 AN: 3380

South Asian (SAS) AF: 0.00 AC: 0 AN: 3388

European-Finnish (FIN) AF: 0.00671 AC: 55 AN: 8200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 140

European-Non Finnish (NFE) AF: 0.00231 AC: 108 AN: 46852

Other (OTH) AF: 0.000779 AC: 1 AN: 1284

Alfa AF: 0.000374 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00110 AC: 133

EpiCase AF: 0.000981

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Supraventricular tachycardia;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.019	D
Polyphen		0.92	P
Vest4		0.56
MVP		0.87
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.60
gMVP		0.47
Mutation Taster		=84/16	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: rs144022614; hg19: chr20-42788571; COSMIC: COSV65904624;