16-87644281-G-A

Position:

• chr16-87644281-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020655.4(JPH3):​c.406G>A​(p.Gly136Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00224 in 1,610,654 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0023 (14 hom.)
• Consequence: JPH3 NM_020655.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.93

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0101519525).
• BP6: Variant 16-87644281-G-A is Benign according to our data. Variant chr16-87644281-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1284993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-87644281-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH3	NM_020655.4	c.406G>A	p.Gly136Ser	missense_variant	2/5	ENST00000284262.3
JPH3	NR_073379.3	n.120G>A		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH3	ENST00000284262.3	c.406G>A	p.Gly136Ser	missense_variant	2/5	1	NM_020655.4	P1
JPH3	ENST00000537256.5	n.120G>A		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00252 AC: 613 AN: 243064 Hom.: 5 AF XY: 0.00246 AC XY: 325 AN XY: 132332

Gnomad AFR exome AF: 0.000449

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.0271

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00220

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00228 AC: 3320 AN: 1458296 Hom.: 14 Cov.: 32 AF XY: 0.00237 AC XY: 1715 AN XY: 725142

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000988

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.00187

Gnomad4 OTH exome AF: 0.00406

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152358 Hom.: 0 Cov.: 34 AF XY: 0.00173 AC XY: 129 AN XY: 74502

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00213

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00283 Hom.: 4

Bravo AF: 0.00196

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00227 AC: 275

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00303

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	JPH3: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.99	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.049
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.14	B
Vest4		0.37
MVP		0.53
MPC		1.3
ClinPred		0.015	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs149647215; hg19: chr16-87677887;