rs28929478

Variant names:

• chr12-110281857-G-A
• rs28929478
• NM_170665.4:c.68G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM2 PP2 PP3_Strong PP5_Moderate

The NM_170665.4(ATP2A2):​c.68G>A​(p.Gly23Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000490417: "In addition, functional studies of the G23E mutation have shown that it results in misfolding of the protein leading to reduced protein expression, and to increased cellular stress and apoptosis in keratinocytes (Wang et al., 2011" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP2A2 NM_170665.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.34
• Publications: 12 publications found

Genes affected

ATP2A2 (HGNC:812): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of the skeletal muscle. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol into the sarcoplasmic reticulum lumen, and is involved in regulation of the contraction/relaxation cycle. Mutations in this gene cause Darier-White disease, also known as keratosis follicularis, an autosomal dominant skin disorder characterized by loss of adhesion between epidermal cells and abnormal keratinization. Other types of mutations in this gene have been associated with various forms of muscular dystrophies. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

ATP2A2 Gene-Disease associations (from GenCC):

• acrokeratosis verruciformis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Darier disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000490417: "In addition, functional studies of the G23E mutation have shown that it results in misfolding of the protein leading to reduced protein expression, and to increased cellular stress and apoptosis in keratinocytes (Wang et al., 2011; Dode et al., 2003)."
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ATP2A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 28 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 4.8777 (above the threshold of 3.09). Trascript score misZ: 7.0223 (above the threshold of 3.09). GenCC associations: The gene is linked to Darier disease, acrokeratosis verruciformis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 12-110281857-G-A is Pathogenic according to our data. Variant chr12-110281857-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17789.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170665.4. 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
	ATP2A2	NM_170665.4	MANE Select	c.68G>A	p.Gly23Glu	missense	Exon 1 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413013.1		c.68G>A	p.Gly23Glu	missense	Exon 1 of 19	NP_001399942.1
	ATP2A2	NM_001413014.1		c.68G>A	p.Gly23Glu	missense	Exon 1 of 22	NP_001399943.1	P16615-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	ENST00000539276.7	TSL:1 MANE Select	c.68G>A	p.Gly23Glu	missense	Exon 1 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.68G>A	p.Gly23Glu	missense	Exon 1 of 21	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000943653.1		c.68G>A	p.Gly23Glu	missense	Exon 2 of 21	ENSP00000613712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1423364 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 705200

African (AFR) AF: 0.00 AC: 0 AN: 30980

American (AMR) AF: 0.00 AC: 0 AN: 39294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24896

East Asian (EAS) AF: 0.00 AC: 0 AN: 37086

South Asian (SAS) AF: 0.00 AC: 0 AN: 80458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094822

Other (OTH) AF: 0.00 AC: 0 AN: 58904

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000222 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Keratosis follicularis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	5.1	H
PhyloP100		6.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.84		Gain of catalytic residue at E20 (P = 0.0037)
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.99
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs28929478; hg19: chr12-110719662;