rs577127824

Variant names:

• chr12-110281550-G-A
• rs577127824
• NM_170665.4:c.-240G>A

Variant summary

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

The NM_170665.4(ATP2A2):​c.-240G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 267,932 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (2 hom.)
• Consequence: ATP2A2 NM_170665.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.243
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Darier disease

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-110281550-G-A is Benign according to our data. Variant chr12-110281550-G-A is described in ClinVar as Benign. ClinVar VariationId is 307154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 827 AD gene.

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.-240G>A		5_prime_UTR	Exon 1 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413013.1		c.-240G>A		5_prime_UTR	Exon 1 of 19	NP_001399942.1
	ATP2A2	NM_001413014.1		c.-240G>A		5_prime_UTR	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.-240G>A		5_prime_UTR	Exon 1 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.-240G>A		5_prime_UTR	Exon 1 of 21	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000943653.1		c.-240G>A		5_prime_UTR	Exon 2 of 21	ENSP00000613712.1

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 827 AN: 151772 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00532 AC: 617 AN: 116054 Hom.: 2 Cov.: 0 AF XY: 0.00508 AC XY: 304 AN XY: 59794

African (AFR) AF: 0.000994 AC: 3 AN: 3018

American (AMR) AF: 0.00391 AC: 10 AN: 2560

Ashkenazi Jewish (ASJ) AF: 0.000245 AC: 1 AN: 4084

East Asian (EAS) AF: 0.00 AC: 0 AN: 8856

South Asian (SAS) AF: 0.00145 AC: 8 AN: 5520

European-Finnish (FIN) AF: 0.0220 AC: 207 AN: 9418

Middle Eastern (MID) AF: 0.00171 AC: 1 AN: 584

European-Non Finnish (NFE) AF: 0.00482 AC: 359 AN: 74542

Other (OTH) AF: 0.00375 AC: 28 AN: 7472

GnomAD4 genome AF: 0.00545 AC: 827 AN: 151878 Hom.: 4 Cov.: 32 AF XY: 0.00647 AC XY: 480 AN XY: 74236

African (AFR) AF: 0.00113 AC: 47 AN: 41514

American (AMR) AF: 0.00347 AC: 53 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5102

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4822

European-Finnish (FIN) AF: 0.0308 AC: 324 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00545 AC: 370 AN: 67850

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00796 Hom.: 1

Bravo AF: 0.00341

Asia WGS AF: 0.00175 AC: 6 AN: 3436

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		0.24
PromoterAI		-0.095	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs577127824; hg19: chr12-110719355;