rs12297171

Variant names:

• chr12-110346414-C-G
• rs12297171
• NM_170665.4:c.3073C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-110346414-C-G
• chr12-110346414-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_170665.4(ATP2A2):​c.3073C>G​(p.Leu1025Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2A2 NM_170665.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.66
• Publications: 2 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), Orphanet, PanelApp Australia, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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 acrokeratosis verruciformis, Darier disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26013112).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	NM_170665.4	MANE Select	c.3073C>G	p.Leu1025Val	missense	Exon 20 of 20	NP_733765.1
	ATP2A2	NM_001413013.1		c.2968C>G	p.Leu990Val	missense	Exon 19 of 19	NP_001399942.1
	ATP2A2	NM_001413015.1		c.2698C>G	p.Leu900Val	missense	Exon 20 of 20	NP_001399944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	ENST00000539276.7	TSL:1 MANE Select	c.3073C>G	p.Leu1025Val	missense	Exon 20 of 20	ENSP00000440045.2
	ATP2A2	ENST00000313432.5	TSL:1	n.896C>G		non_coding_transcript_exon	Exon 2 of 2
	ATP2A2	ENST00000308664.10	TSL:1	c.2980+93C>G		intron	N/A	ENSP00000311186.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.056	D
MutationAssessor	Benign	1.0	L
PhyloP100		2.7
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.036	D
Polyphen		0.29	B
Vest4		0.23
MutPred		0.28		Gain of catalytic residue at P1024 (P = 0.0028)
MVP		0.68
MPC		0.48
ClinPred		0.38	T
GERP RS		4.2
PromoterAI		-0.0097	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.80
Mutation Taster		=53/47	polymorphism

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: rs12297171; hg19: chr12-110784219;