16-87604287-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr16-87604287-C-CCTGCTGCTGCTG
• rs71156237
• NM_020655.4:c.382+790_382+801dupCTGCTGCTGCTG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_001271604.4(JPH3):​c.461_472dupCTGCTGCTGCTG​(p.Ala154_Ala157dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 0)
  • Exomes 𝑓: 0.0084 (103 hom.)
  • Failed GnomAD Quality Control
• Consequence: JPH3 NM_001271604.4 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• 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 -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001271604.4
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0156 (2348/150050) while in subpopulation AFR AF = 0.0349 (1419/40662). AF 95% confidence interval is 0.0334. There are 28 homozygotes in GnomAd4. There are 1128 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2348 AD gene.

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+790_382+801dupCTGCTGCTGCTG		intron	N/A	NP_065706.2
	JPH3	NM_001271604.4		c.461_472dupCTGCTGCTGCTG	p.Ala154_Ala157dup	disruptive_inframe_insertion	Exon 2 of 2	NP_001258533.1
	JPH3	NM_001271605.3		c.*159_*170dupCTGCTGCTGCTG		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+790_382+801dupCTGCTGCTGCTG		intron	N/A	ENSP00000284262.2
	JPH3	ENST00000301008.5	TSL:1	n.721_732dupCTGCTGCTGCTG		non_coding_transcript_exon	Exon 2 of 2
	JPH3	ENST00000537256.5	TSL:2	n.96+2388_96+2399dupCTGCTGCTGCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2346 AN: 149942 Hom.: 28 Cov.: 0

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00972

Gnomad ASJ AF: 0.00638

Gnomad EAS AF: 0.00630

Gnomad SAS AF: 0.00170

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00870

Gnomad OTH AF: 0.0127

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00840 AC: 10772 AN: 1282142 Hom.: 103 Cov.: 30 AF XY: 0.00824 AC XY: 5212 AN XY: 632666

African (AFR) AF: 0.0410 AC: 1156 AN: 28180

American (AMR) AF: 0.00853 AC: 276 AN: 32372

Ashkenazi Jewish (ASJ) AF: 0.00467 AC: 101 AN: 21650

East Asian (EAS) AF: 0.00736 AC: 177 AN: 24064

South Asian (SAS) AF: 0.00374 AC: 291 AN: 77810

European-Finnish (FIN) AF: 0.00939 AC: 276 AN: 29386

Middle Eastern (MID) AF: 0.00830 AC: 42 AN: 5058

European-Non Finnish (NFE) AF: 0.00785 AC: 7951 AN: 1012582

Other (OTH) AF: 0.00984 AC: 502 AN: 51040

GnomAD4 genome AF: 0.0156 AC: 2348 AN: 150050 Hom.: 28 Cov.: 0 AF XY: 0.0154 AC XY: 1128 AN XY: 73212

African (AFR) AF: 0.0349 AC: 1419 AN: 40662

American (AMR) AF: 0.00970 AC: 147 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00638 AC: 22 AN: 3448

East Asian (EAS) AF: 0.00632 AC: 32 AN: 5062

South Asian (SAS) AF: 0.00170 AC: 8 AN: 4710

European-Finnish (FIN) AF: 0.0101 AC: 104 AN: 10300

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00870 AC: 587 AN: 67452

Other (OTH) AF: 0.0125 AC: 26 AN: 2076

Alfa AF: 0.00948 Hom.: 316

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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;