chr16-87604287-CCTGCTGCTGCTG-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001271604.4(JPH3):​c.461_472delCTGCTGCTGCTG​(p.Ala154_Ala157del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 1,432,572 control chromosomes in the GnomAD database, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_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 0.00091 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: JPH3 NM_001271604.4 disruptive_inframe_deletion
• 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: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001271604.4
• BS2: High AC in GnomAd4 at 136 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+801delCTGCTGCTGCTG		intron	N/A	NP_065706.2
	JPH3	NM_001271604.4		c.461_472delCTGCTGCTGCTG	p.Ala154_Ala157del	disruptive_inframe_deletion	Exon 2 of 2	NP_001258533.1	F8W9A3
	JPH3	NM_001271605.3		c.*159_*170delCTGCTGCTGCTG		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+801delCTGCTGCTGCTG		intron	N/A	ENSP00000284262.2	Q8WXH2-1
	JPH3	ENST00000301008.5	TSL:1	n.721_732delCTGCTGCTGCTG		non_coding_transcript_exon	Exon 2 of 2
	JPH3	ENST00000537256.5	TSL:2	n.96+2388_96+2399delCTGCTGCTGCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 135 AN: 149956 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.000985

Gnomad SAS AF: 0.000636

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000608

Gnomad OTH AF: 0.00146

GnomAD4 exome AF: 0.000579 AC: 743 AN: 1282508 Hom.: 2 AF XY: 0.000597 AC XY: 378 AN XY: 632830

African (AFR) AF: 0.00194 AC: 55 AN: 28328

American (AMR) AF: 0.00117 AC: 38 AN: 32398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21658

East Asian (EAS) AF: 0.000291 AC: 7 AN: 24078

South Asian (SAS) AF: 0.00121 AC: 94 AN: 77822

European-Finnish (FIN) AF: 0.000102 AC: 3 AN: 29360

Middle Eastern (MID) AF: 0.00790 AC: 40 AN: 5062

European-Non Finnish (NFE) AF: 0.000457 AC: 463 AN: 1012744

Other (OTH) AF: 0.000842 AC: 43 AN: 51058

GnomAD4 genome AF: 0.000906 AC: 136 AN: 150064 Hom.: 0 Cov.: 0 AF XY: 0.000819 AC XY: 60 AN XY: 73220

African (AFR) AF: 0.00152 AC: 62 AN: 40668

American (AMR) AF: 0.00112 AC: 17 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.000290 AC: 1 AN: 3448

East Asian (EAS) AF: 0.000988 AC: 5 AN: 5062

South Asian (SAS) AF: 0.000637 AC: 3 AN: 4710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10302

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000608 AC: 41 AN: 67456

Other (OTH) AF: 0.00145 AC: 3 AN: 2076

Alfa AF: 0.00 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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs71156237; hg19: chr16-87637893;