16-87604287-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr16-87604287-C-CCTG
• rs71156237
• NM_020655.4:c.382+799_382+801dupCTG

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP3 BP6_Moderate BA1

The NM_001271604.4(JPH3):​c.470_472dupCTG​(p.Ala157dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,357,458 control chromosomes in the GnomAD database, including 1,783 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.091 (692 hom., cov: 0)
  • Exomes 𝑓: 0.078 (1091 hom.)
• Consequence: JPH3 NM_001271604.4 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.966
• Publications: 1 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 -11 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001271604.4
• BP6: Variant 16-87604287-C-CCTG is Benign according to our data. Variant chr16-87604287-C-CCTG is described in ClinVar as Likely_benign. ClinVar VariationId is 3911194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271604.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH3	NM_020655.4	MANE Select	c.382+799_382+801dupCTG		intron	N/A	NP_065706.2
	JPH3	NM_001271604.4		c.470_472dupCTG	p.Ala157dup	disruptive_inframe_insertion	Exon 2 of 2	NP_001258533.1
	JPH3	NM_001271605.3		c.*168_*170dupCTG		3_prime_UTR	Exon 2 of 2	NP_001258534.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH3	ENST00000284262.3	TSL:1 MANE Select	c.382+799_382+801dupCTG		intron	N/A	ENSP00000284262.2
	JPH3	ENST00000301008.5	TSL:1	n.730_732dupCTG		non_coding_transcript_exon	Exon 2 of 2
	JPH3	ENST00000537256.5	TSL:2	n.96+2397_96+2399dupCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0905 AC: 13564 AN: 149802 Hom.: 689 Cov.: 0

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00778

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0639

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.0911

Gnomad FIN AF: 0.0671

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0636

Gnomad OTH AF: 0.0844

GnomAD4 exome AF: 0.0776 AC: 93738 AN: 1207548 Hom.: 1091 Cov.: 30 AF XY: 0.0776 AC XY: 46097 AN XY: 594012

African (AFR) AF: 0.126 AC: 3476 AN: 27640

American (AMR) AF: 0.143 AC: 4469 AN: 31198

Ashkenazi Jewish (ASJ) AF: 0.0819 AC: 1593 AN: 19446

East Asian (EAS) AF: 0.200 AC: 4714 AN: 23612

South Asian (SAS) AF: 0.0972 AC: 6913 AN: 71108

European-Finnish (FIN) AF: 0.0814 AC: 2182 AN: 26796

Middle Eastern (MID) AF: 0.0671 AC: 319 AN: 4752

European-Non Finnish (NFE) AF: 0.0691 AC: 66026 AN: 954956

Other (OTH) AF: 0.0842 AC: 4046 AN: 48040

GnomAD4 genome AF: 0.0906 AC: 13583 AN: 149910 Hom.: 692 Cov.: 0 AF XY: 0.0912 AC XY: 6668 AN XY: 73148

African (AFR) AF: 0.128 AC: 5198 AN: 40654

American (AMR) AF: 0.107 AC: 1626 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 220 AN: 3444

East Asian (EAS) AF: 0.185 AC: 935 AN: 5062

South Asian (SAS) AF: 0.0908 AC: 427 AN: 4704

European-Finnish (FIN) AF: 0.0671 AC: 688 AN: 10246

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0636 AC: 4289 AN: 67394

Other (OTH) AF: 0.0859 AC: 178 AN: 2072

Alfa AF: 0.0863 Hom.: 316

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs71156237; hg19: chr16-87637893; COSMIC: COSV52465413; COSMIC: COSV52465413;