rs121912732

Variant names:

• chr12-110342430-A-G
• rs121912732
• NM_170665.4:c.2300A>G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_170665.4(ATP2A2):​c.2300A>G​(p.Asn767Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000582773: Published functional studies demonstrate a damaging effect on protein function (PMID:16766529)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N767D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP2A2 NM_170665.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32
• Publications: 14 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000582773: Published functional studies demonstrate a damaging effect on protein function (PMID: 16766529)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-110342429-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 546106.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.944
• PP5: Variant 12-110342430-A-G is Pathogenic according to our data. Variant chr12-110342430-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2300A>G	p.Asn767Ser	missense	Exon 15 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413013.1		c.2195A>G	p.Asn732Ser	missense	Exon 14 of 19	NP_001399942.1
	ATP2A2	NM_001413014.1		c.2300A>G	p.Asn767Ser	missense	Exon 15 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.2300A>G	p.Asn767Ser	missense	Exon 15 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.2300A>G	p.Asn767Ser	missense	Exon 15 of 21	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000943653.1		c.2300A>G	p.Asn767Ser	missense	Exon 16 of 21	ENSP00000613712.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461428 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727030

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Darier disease, acral hemorrhagic type (1)
1	-	-	Keratosis follicularis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.75		Gain of catalytic residue at E770 (P = 6e-04)
MVP		0.94
MPC		2.0
ClinPred		0.97	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912732; hg19: chr12-110780235;