20-44114658-G-A

Variant names:

• chr20-44114658-G-A
• rs115154926
• NM_020433.5:c.*14+124C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020433.5(JPH2):​c.*14+124C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 679,824 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: JPH2 NM_020433.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.551
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-44114658-G-A is Benign according to our data. Variant chr20-44114658-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 675764.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00491 (741/151064) while in subpopulation AFR AF = 0.0173 (712/41154). AF 95% confidence interval is 0.0162. There are 10 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 SD,AD,Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH2	NM_020433.5	c.*14+124C>T		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+124C>T		intron_variant	Intron 5 of 5	5	NM_020433.5	ENSP00000362071.3

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 740 AN: 150950 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

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: 0.0000442

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.000753 AC: 398 AN: 528760 Hom.: 1 AF XY: 0.000601 AC XY: 171 AN XY: 284376

African (AFR) AF: 0.0193 AC: 292 AN: 15102

American (AMR) AF: 0.00140 AC: 46 AN: 32872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17586

East Asian (EAS) AF: 0.00 AC: 0 AN: 29054

South Asian (SAS) AF: 0.000168 AC: 10 AN: 59662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2266

European-Non Finnish (NFE) AF: 0.0000129 AC: 4 AN: 310504

Other (OTH) AF: 0.00162 AC: 46 AN: 28394

GnomAD4 genome AF: 0.00491 AC: 741 AN: 151064 Hom.: 10 Cov.: 31 AF XY: 0.00487 AC XY: 359 AN XY: 73710

African (AFR) AF: 0.0173 AC: 712 AN: 41154

American (AMR) AF: 0.00146 AC: 22 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67822

Other (OTH) AF: 0.00191 AC: 4 AN: 2096

Alfa AF: 0.00333 Hom.: 0

Bravo AF: 0.00584

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.57
PhyloP100		0.55
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: rs115154926; hg19: chr20-42743298;