16-87644280-C-T

Variant names:

• chr16-87644280-C-T
• rs79690276
• NM_020655.4:c.405C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020655.4(JPH3):​c.405C>T​(p.Val135Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,610,232 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 34)
  • Exomes 𝑓: 0.0018 (44 hom.)
• Consequence: JPH3 NM_020655.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.583

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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 16-87644280-C-T is Benign according to our data. Variant chr16-87644280-C-T is described in ClinVar as [Benign]. Clinvar id is 786946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.583 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1998/152386) while in subpopulation AFR AF = 0.0436 (1812/41598). AF 95% confidence interval is 0.0419. There are 45 homozygotes in GnomAd4. There are 906 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1998 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JPH3	NM_020655.4	c.405C>T	p.Val135Val	synonymous_variant	Exon 2 of 5	ENST00000284262.3	NP_065706.2
JPH3	NR_073379.3	n.119C>T		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.405C>T	p.Val135Val	synonymous_variant	Exon 2 of 5	1	NM_020655.4	ENSP00000284262.2
JPH3	ENST00000537256.5	n.119C>T		non_coding_transcript_exon_variant	Exon 2 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1993 AN: 152268 Hom.: 45 Cov.: 34

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00431 AC: 1044 AN: 242420 AF XY: 0.00382

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00225

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000234

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00180 AC: 2627 AN: 1457846 Hom.: 44 Cov.: 32 AF XY: 0.00188 AC XY: 1364 AN XY: 724920

Gnomad4 AFR exome AF: 0.0457 AC: 1528 AN: 33438

Gnomad4 AMR exome AF: 0.00231 AC: 103 AN: 44504

Gnomad4 ASJ exome AF: 0.0000774 AC: 2 AN: 25836

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39666

Gnomad4 SAS exome AF: 0.00684 AC: 586 AN: 85650

Gnomad4 FIN exome AF: 0.000134 AC: 7 AN: 52202

Gnomad4 NFE exome AF: 0.000155 AC: 172 AN: 1110554

Gnomad4 Remaining exome AF: 0.00350 AC: 211 AN: 60242

GnomAD4 genome AF: 0.0131 AC: 1998 AN: 152386 Hom.: 45 Cov.: 34 AF XY: 0.0122 AC XY: 906 AN XY: 74516

Gnomad4 AFR AF: 0.0436 AC: 0.0435598 AN: 0.0435598

Gnomad4 AMR AF: 0.00718 AC: 0.00718485 AN: 0.00718485

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000193 AC: 0.000192827 AN: 0.000192827

Gnomad4 SAS AF: 0.00579 AC: 0.0057947 AN: 0.0057947

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000309 AC: 0.00030866 AN: 0.00030866

Gnomad4 OTH AF: 0.0118 AC: 0.0118147 AN: 0.0118147

Alfa AF: 0.00495 Hom.: 11

Bravo AF: 0.0145

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000475

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	7.6
DANN	Benign	0.66
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

Publications

LitVar

Other links and lift over

dbSNP: rs79690276; hg19: chr16-87677886; COSMIC: COSV52468857;