20-44186291-T-C

Variant names:

• chr20-44186291-T-C
• rs6031442
• NM_020433.5:c.379+36A>G

Variant summary

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

The ENST00000372980.4(JPH2):​c.379+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 1,604,436 control chromosomes in the GnomAD database, including 561,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56211 hom., cov: 27)
  • Exomes 𝑓: 0.83 (505623 hom.)
• Consequence: JPH2 ENST00000372980.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.491
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 20-44186291-T-C is Benign according to our data. Variant chr20-44186291-T-C is described in ClinVar as Benign. ClinVar VariationId is 671113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372980.4. 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.379+36A>G		intron	N/A	NP_065166.2
	JPH2	NM_175913.4		c.379+36A>G		intron	N/A	NP_787109.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.379+36A>G		intron	N/A	ENSP00000362071.3
	JPH2	ENST00000342272.3	TSL:1	c.379+36A>G		intron	N/A	ENSP00000344590.3

Frequencies

GnomAD3 genomes AF: 0.860 AC: 130244 AN: 151422 Hom.: 56157 Cov.: 27

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.869

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.836

Gnomad MID AF: 0.818

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.862

GnomAD2 exomes AF: 0.847 AC: 206046 AN: 243244 AF XY: 0.842

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.907

Gnomad ASJ exome AF: 0.832

Gnomad EAS exome AF: 0.828

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.824

Gnomad OTH exome AF: 0.837

GnomAD4 exome AF: 0.834 AC: 1211015 AN: 1452896 Hom.: 505623 Cov.: 40 AF XY: 0.833 AC XY: 602277 AN XY: 723012

African (AFR) AF: 0.927 AC: 30944 AN: 33372

American (AMR) AF: 0.903 AC: 40199 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 21721 AN: 26010

East Asian (EAS) AF: 0.877 AC: 34814 AN: 39692

South Asian (SAS) AF: 0.846 AC: 72848 AN: 86100

European-Finnish (FIN) AF: 0.835 AC: 39114 AN: 46816

Middle Eastern (MID) AF: 0.845 AC: 4831 AN: 5716

European-Non Finnish (NFE) AF: 0.825 AC: 916279 AN: 1110416

Other (OTH) AF: 0.834 AC: 50265 AN: 60262

GnomAD4 genome AF: 0.860 AC: 130358 AN: 151540 Hom.: 56211 Cov.: 27 AF XY: 0.860 AC XY: 63694 AN XY: 74030

African (AFR) AF: 0.928 AC: 38308 AN: 41268

American (AMR) AF: 0.869 AC: 13256 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2858 AN: 3468

East Asian (EAS) AF: 0.832 AC: 4208 AN: 5058

South Asian (SAS) AF: 0.834 AC: 3992 AN: 4786

European-Finnish (FIN) AF: 0.836 AC: 8820 AN: 10544

Middle Eastern (MID) AF: 0.815 AC: 238 AN: 292

European-Non Finnish (NFE) AF: 0.828 AC: 56203 AN: 67858

Other (OTH) AF: 0.862 AC: 1816 AN: 2106

Alfa AF: 0.847 Hom.: 10298

Bravo AF: 0.865

Asia WGS AF: 0.829 AC: 2884 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	5.1
DANN	Benign	0.32
PhyloP100		-0.49
Mutation Taster		=16/84	disease causing

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: rs6031442; hg19: chr20-42814931;