20-44118607-C-T

Variant names:

• chr20-44118607-C-T
• rs3810510
• NM_020433.5:c.1186G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020433.5(JPH2):​c.1186G>A​(p.Ala396Thr) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,610,126 control chromosomes in the GnomAD database, including 23,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A396A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3808 hom., cov: 33)
  • Exomes 𝑓: 0.15 (19449 hom.)
• Consequence: JPH2 NM_020433.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.34
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001573354).
• BP6: Variant 20-44118607-C-T is Benign according to our data. Variant chr20-44118607-C-T is described in ClinVar as Benign. ClinVar VariationId is 137607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 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.1186G>A	p.Ala396Thr	missense	Exon 3 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.1186G>A	p.Ala396Thr	missense	Exon 3 of 6	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.1267G>A	p.Ala423Thr	missense	Exon 4 of 7	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.1249G>A	p.Ala417Thr	missense	Exon 4 of 7	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30543 AN: 152098 Hom.: 3802 Cov.: 33

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.192

GnomAD2 exomes AF: 0.178 AC: 44187 AN: 248698 AF XY: 0.183

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.0969

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.146 AC: 212865 AN: 1457908 Hom.: 19449 Cov.: 33 AF XY: 0.150 AC XY: 109141 AN XY: 725510

African (AFR) AF: 0.349 AC: 11677 AN: 33450

American (AMR) AF: 0.102 AC: 4547 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3996 AN: 26130

East Asian (EAS) AF: 0.411 AC: 16311 AN: 39696

South Asian (SAS) AF: 0.282 AC: 24293 AN: 86244

European-Finnish (FIN) AF: 0.102 AC: 5102 AN: 50114

Middle Eastern (MID) AF: 0.199 AC: 1147 AN: 5758

European-Non Finnish (NFE) AF: 0.123 AC: 136375 AN: 1111468

Other (OTH) AF: 0.156 AC: 9417 AN: 60326

GnomAD4 genome AF: 0.201 AC: 30565 AN: 152218 Hom.: 3808 Cov.: 33 AF XY: 0.200 AC XY: 14912 AN XY: 74438

African (AFR) AF: 0.336 AC: 13961 AN: 41506

American (AMR) AF: 0.143 AC: 2184 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 497 AN: 3472

East Asian (EAS) AF: 0.365 AC: 1889 AN: 5178

South Asian (SAS) AF: 0.280 AC: 1352 AN: 4828

European-Finnish (FIN) AF: 0.107 AC: 1140 AN: 10606

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.132 AC: 8998 AN: 68008

Other (OTH) AF: 0.198 AC: 418 AN: 2114

Alfa AF: 0.160 Hom.: 9318

Bravo AF: 0.208

TwinsUK AF: 0.118 AC: 436

ALSPAC AF: 0.122 AC: 469

ESP6500AA AF: 0.330 AC: 1455

ESP6500EA AF: 0.129 AC: 1109

ExAC AF: 0.184 AC: 22344

Asia WGS AF: 0.311 AC: 1082 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.146

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hypertrophic cardiomyopathy 17 (2)
-	-	1	Cardiomyopathy, dilated, 2E (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.17
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.97	D
Vest4		0.17
ClinPred		0.027	T
GERP RS		3.8
Varity_R		0.17
gMVP		0.75
Mutation Taster		=58/42	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: rs3810510; hg19: chr20-42747247; COSMIC: COSV65903111;