16-87604287-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr16-87604287-C-CCTGCTG
• rs71156237
• NM_020655.4:c.382+796_382+801dupCTGCTG

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.467_472dupCTGCTG​(p.Ala156_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 0.269 in 1,424,918 control chromosomes in the GnomAD database, including 23,841 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5340 hom., cov: 0)
  • Exomes 𝑓: 0.27 (18501 hom.)
• Consequence: JPH3 NM_001271604.4 disruptive_inframe_insertion
• Clinical Significance: 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-CCTGCTG is Benign according to our data. Variant chr16-87604287-C-CCTGCTG is described in ClinVar as Benign. ClinVar VariationId is 3911196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 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+796_382+801dupCTGCTG		intron	N/A	NP_065706.2
	JPH3	NM_001271604.4		c.467_472dupCTGCTG	p.Ala156_Ala157dup	disruptive_inframe_insertion	Exon 2 of 2	NP_001258533.1
	JPH3	NM_001271605.3		c.*165_*170dupCTGCTG		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+796_382+801dupCTGCTG		intron	N/A	ENSP00000284262.2
	JPH3	ENST00000301008.5	TSL:1	n.727_732dupCTGCTG		non_coding_transcript_exon	Exon 2 of 2
	JPH3	ENST00000537256.5	TSL:2	n.96+2394_96+2399dupCTGCTG		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.258 AC: 38590 AN: 149850 Hom.: 5341 Cov.: 0

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.0923

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.285

GnomAD4 exome AF: 0.270 AC: 344416 AN: 1274960 Hom.: 18501 Cov.: 30 AF XY: 0.272 AC XY: 171239 AN XY: 629186

African (AFR) AF: 0.169 AC: 4739 AN: 27994

American (AMR) AF: 0.187 AC: 6031 AN: 32296

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 7376 AN: 21574

East Asian (EAS) AF: 0.134 AC: 3224 AN: 23984

South Asian (SAS) AF: 0.276 AC: 21458 AN: 77672

European-Finnish (FIN) AF: 0.322 AC: 9362 AN: 29110

Middle Eastern (MID) AF: 0.322 AC: 1624 AN: 5042

European-Non Finnish (NFE) AF: 0.275 AC: 276850 AN: 1006592

Other (OTH) AF: 0.271 AC: 13752 AN: 50696

GnomAD4 genome AF: 0.257 AC: 38600 AN: 149958 Hom.: 5340 Cov.: 0 AF XY: 0.258 AC XY: 18882 AN XY: 73160

African (AFR) AF: 0.172 AC: 6974 AN: 40638

American (AMR) AF: 0.213 AC: 3226 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1251 AN: 3446

East Asian (EAS) AF: 0.0925 AC: 468 AN: 5058

South Asian (SAS) AF: 0.303 AC: 1425 AN: 4706

European-Finnish (FIN) AF: 0.322 AC: 3319 AN: 10294

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.311 AC: 20983 AN: 67414

Other (OTH) AF: 0.284 AC: 588 AN: 2074

Alfa AF: 0.249 Hom.: 316

ClinVar

ClinVar submissions as Germline

Significance: 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: COSV52464194; COSMIC: COSV52464194;