rs9934222

Variant names:

• chr16-87644643-G-A
• rs9934222
• NM_020655.4:c.768G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_020655.4(JPH3):​c.768G>A​(p.Thr256Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,611,644 control chromosomes in the GnomAD database, including 16,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (1624 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14852 hom.)
• Consequence: JPH3 NM_020655.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0730
• Publications: 10 publications found

Genes affected

JPH3 (HGNC:14203): (junctophilin 3) 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. CAG/CTG repeat expansion from normally 6-28 repeats to 40-59 repeats in the 3' UTR of this gene have been associated with Huntington disease-like 2 (HDL2). This gene is a member of the junctophilin gene family. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2016]

JPH3 Gene-Disease associations (from GenCC):

• Huntington disease-like 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-87644643-G-A is Benign according to our data. Variant chr16-87644643-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059867.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.073 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH3	NM_020655.4	c.768G>A	p.Thr256Thr	synonymous_variant	Exon 2 of 5	ENST00000284262.3	NP_065706.2
JPH3	NR_073379.3	n.482G>A		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JPH3	ENST00000284262.3	c.768G>A	p.Thr256Thr	synonymous_variant	Exon 2 of 5	1	NM_020655.4	ENSP00000284262.2
JPH3	ENST00000537256.5	n.482G>A		non_coding_transcript_exon_variant	Exon 2 of 6	2

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21173 AN: 151976 Hom.: 1625 Cov.: 33

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.000972

Gnomad SAS AF: 0.0735

Gnomad FIN AF: 0.0910

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.113 AC: 28145 AN: 248042 AF XY: 0.113

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.00110

Gnomad FIN exome AF: 0.0861

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.138 AC: 201731 AN: 1459550 Hom.: 14852 Cov.: 60 AF XY: 0.137 AC XY: 99371 AN XY: 726148

African (AFR) AF: 0.170 AC: 5683 AN: 33474

American (AMR) AF: 0.0796 AC: 3561 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2767 AN: 26118

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39692

South Asian (SAS) AF: 0.0758 AC: 6535 AN: 86250

European-Finnish (FIN) AF: 0.0854 AC: 4375 AN: 51256

Middle Eastern (MID) AF: 0.170 AC: 978 AN: 5768

European-Non Finnish (NFE) AF: 0.153 AC: 169906 AN: 1111900

Other (OTH) AF: 0.131 AC: 7899 AN: 60372

GnomAD4 genome AF: 0.139 AC: 21181 AN: 152094 Hom.: 1624 Cov.: 33 AF XY: 0.133 AC XY: 9874 AN XY: 74338

African (AFR) AF: 0.167 AC: 6933 AN: 41482

American (AMR) AF: 0.104 AC: 1586 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

East Asian (EAS) AF: 0.000974 AC: 5 AN: 5134

South Asian (SAS) AF: 0.0736 AC: 355 AN: 4824

European-Finnish (FIN) AF: 0.0910 AC: 964 AN: 10596

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.154 AC: 10474 AN: 67984

Other (OTH) AF: 0.135 AC: 284 AN: 2110

Alfa AF: 0.146 Hom.: 1008

Bravo AF: 0.140

Asia WGS AF: 0.0460 AC: 162 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.155

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

JPH3-related disorder Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.4
DANN	Benign	0.87
PhyloP100		-0.073
Mutation Taster		=100/0	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: rs9934222; hg19: chr16-87678249; COSMIC: COSV52467784;