20-44160416-G-C

Variant names:

• chr20-44160416-G-C
• rs111987307
• NM_020433.5:c.380-9C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020433.5(JPH2):​c.380-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,608,122 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (22 hom.)
• Consequence: JPH2 NM_020433.5 intron
• Scores: Splicing: ADA: 0.00007931
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.421
• Publications: 3 publications found

Genes affected

JPH2 (HGNC:14202): (junctophilin 2) 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. This gene is a member of the junctophilin gene family. Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described. [provided by RefSeq, Jul 2008]

JPH2 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: SD, AR, AD Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen
• cardiomyopathy, dilated, 2E

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-44160416-G-C is Benign according to our data. Variant chr20-44160416-G-C is described in ClinVar as Benign. ClinVar VariationId is 137603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 SD,AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020433.5. 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
	JPH2	NM_020433.5	MANE Select	c.380-9C>G		intron	N/A	NP_065166.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JPH2	ENST00000372980.4	TSL:5 MANE Select	c.380-9C>G		intron	N/A	ENSP00000362071.3	Q9BR39-1
	JPH2	ENST00000900331.1		c.380-9C>G		intron	N/A	ENSP00000570390.1
	JPH2	ENST00000950207.1		c.443-9C>G		intron	N/A	ENSP00000620266.1

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152252 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00458

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00438 AC: 1018 AN: 232644 AF XY: 0.00432

Gnomad AFR exome AF: 0.000357

Gnomad AMR exome AF: 0.000977

Gnomad ASJ exome AF: 0.00618

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00517

GnomAD4 exome AF: 0.00398 AC: 5787 AN: 1455752 Hom.: 22 Cov.: 32 AF XY: 0.00404 AC XY: 2923 AN XY: 723876

African (AFR) AF: 0.000270 AC: 9 AN: 33384

American (AMR) AF: 0.00104 AC: 46 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 163 AN: 25960

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39562

South Asian (SAS) AF: 0.00147 AC: 125 AN: 85218

European-Finnish (FIN) AF: 0.0178 AC: 920 AN: 51662

Middle Eastern (MID) AF: 0.00245 AC: 13 AN: 5312

European-Non Finnish (NFE) AF: 0.00389 AC: 4318 AN: 1110172

Other (OTH) AF: 0.00318 AC: 191 AN: 60134

GnomAD4 genome AF: 0.00411 AC: 627 AN: 152370 Hom.: 2 Cov.: 32 AF XY: 0.00482 AC XY: 359 AN XY: 74510

African (AFR) AF: 0.000457 AC: 19 AN: 41596

American (AMR) AF: 0.00300 AC: 46 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0206 AC: 219 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00459 AC: 312 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00437 Hom.: 0

Bravo AF: 0.00282

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.3
DANN	Benign	0.75
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000079
dbscSNV1_RF	Benign	0.048
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

Other links and lift over

dbSNP: rs111987307; hg19: chr20-42789056;