20-44114609-T-TGC

Variant names:

• chr20-44114609-T-TGC
• rs1555853088
• NM_020433.5:c.*14+171_*14+172dupGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_020433.5(JPH2):​c.*14+171_*14+172dupGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 144,062 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.016 (31 hom., cov: 29)
• Consequence: JPH2 NM_020433.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00600
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 20-44114609-T-TGC is Benign according to our data. Variant chr20-44114609-T-TGC is described in ClinVar as [Likely_benign]. Clinvar id is 1194687.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2333/144062) while in subpopulation NFE AF = 0.0243 (1598/65690). AF 95% confidence interval is 0.0233. There are 31 homozygotes in GnomAd4. There are 1139 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 SD,AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH2	NM_020433.5	c.*14+171_*14+172dupGC		intron_variant	Intron 5 of 5	ENST00000372980.4	NP_065166.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH2	ENST00000372980.4	c.*14+172_*14+173insGC		intron_variant	Intron 5 of 5	5	NM_020433.5	ENSP00000362071.3

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2332 AN: 143962 Hom.: 31 Cov.: 29

Gnomad AFR AF: 0.00416

Gnomad AMI AF: 0.00113

Gnomad AMR AF: 0.00991

Gnomad ASJ AF: 0.00536

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00297

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.0102

Gnomad NFE AF: 0.0243

Gnomad OTH AF: 0.0120

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0162 AC: 2333 AN: 144062 Hom.: 31 Cov.: 29 AF XY: 0.0163 AC XY: 1139 AN XY: 69934

African (AFR) AF: 0.00415 AC: 161 AN: 38828

American (AMR) AF: 0.00990 AC: 142 AN: 14344

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 18 AN: 3356

East Asian (EAS) AF: 0.00175 AC: 8 AN: 4578

South Asian (SAS) AF: 0.00320 AC: 14 AN: 4372

European-Finnish (FIN) AF: 0.0374 AC: 364 AN: 9724

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 274

European-Non Finnish (NFE) AF: 0.0243 AC: 1598 AN: 65690

Other (OTH) AF: 0.0119 AC: 24 AN: 2014

Alfa AF: 0.0153 Hom.: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0060
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555853088; hg19: chr20-42743249;