chr16-87696571-C-G

Position:

• chr16-87696571-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020655.4(JPH3):​c.2167-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,612,372 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (11 hom.)
• Consequence: JPH3 NM_020655.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001323
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.04

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]

KLHDC4 (HGNC:25272): (kelch domain containing 4)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-87696571-C-G is Benign according to our data. Variant chr16-87696571-C-G is described in ClinVar as [Benign]. Clinvar id is 717235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 287 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JPH3	NM_020655.4	c.2167-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000284262.3
JPH3	NR_073379.3	n.1881-9C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JPH3	ENST00000284262.3	c.2167-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020655.4	P1
KLHDC4	ENST00000568444.1	n.302G>C		non_coding_transcript_exon_variant	2/2	3
JPH3	ENST00000537256.5	n.1881-9C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
JPH3	ENST00000563609.1	n.2461-9C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00176 AC: 441 AN: 250200 Hom.: 2 AF XY: 0.00179 AC XY: 242 AN XY: 135316

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00300

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00255 AC: 3729 AN: 1460022 Hom.: 11 Cov.: 30 AF XY: 0.00247 AC XY: 1796 AN XY: 726434

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000210

Gnomad4 NFE exome AF: 0.00310

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.00169 AC XY: 126 AN XY: 74500

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00209

EpiCase AF: 0.00305

EpiControl AF: 0.00391

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.3
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.020		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: rs201540001; hg19: chr16-87730177;