rs782547688

chr17-41757682-C-Achr17-41757682-C-Gchr17-41757682-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_002230.4(JUP):c.1876G>T(p.Ala626Ser) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A626T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JUP	NM_002230.4	c.1876G>T	p.Ala626Ser	missense_variant	11/14	ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8	c.1876G>T	p.Ala626Ser	missense_variant	11/14	1	NM_002230.4	P1
JUP	ENST00000310706.9	c.1876G>T	p.Ala626Ser	missense_variant	11/15	1		P1
JUP	ENST00000393930.5	c.1876G>T	p.Ala626Ser	missense_variant	11/15	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248994 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461278 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.68	P;P;P
Vest4		0.77
MutPred		0.60		Gain of glycosylation at A626 (P = 0.0192);Gain of glycosylation at A626 (P = 0.0192);Gain of glycosylation at A626 (P = 0.0192);
MVP		0.80
MPC		1.1
ClinPred		0.77	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.54
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs782547688; hg19: chr17-39913934;