12-110281387-C-G

Variant names:

• chr12-110281387-C-G
• rs3026433
• NM_170665.4:c.-403C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170665.4(ATP2A2):​c.-403C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 151,672 control chromosomes in the GnomAD database, including 2,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2642 hom., cov: 32)
  • Exomes 𝑓: 0.15 (4 hom.)
• Consequence: ATP2A2 NM_170665.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.153
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-110281387-C-G is Benign according to our data. Variant chr12-110281387-C-G is described in ClinVar as Benign. ClinVar VariationId is 307149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

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.-403C>G		5_prime_UTR	Exon 1 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413013.1		c.-403C>G		5_prime_UTR	Exon 1 of 19	NP_001399942.1
	ATP2A2	NM_001413014.1		c.-403C>G		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.-403C>G		5_prime_UTR	Exon 1 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.-403C>G		5_prime_UTR	Exon 1 of 21	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000943653.1		c.-403C>G		5_prime_UTR	Exon 2 of 21	ENSP00000613712.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24251 AN: 151292 Hom.: 2638 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.00311

Gnomad SAS AF: 0.0903

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.146 AC: 40 AN: 274 Hom.: 4 Cov.: 0 AF XY: 0.142 AC XY: 23 AN XY: 162

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.167 AC: 1 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.333 AC: 2 AN: 6

European-Finnish (FIN) AF: 0.125 AC: 1 AN: 8

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.154 AC: 32 AN: 208

Other (OTH) AF: 0.214 AC: 3 AN: 14

GnomAD4 genome AF: 0.160 AC: 24263 AN: 151398 Hom.: 2642 Cov.: 32 AF XY: 0.162 AC XY: 11967 AN XY: 73994

African (AFR) AF: 0.0398 AC: 1649 AN: 41468

American (AMR) AF: 0.277 AC: 4214 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 262 AN: 3460

East Asian (EAS) AF: 0.00332 AC: 17 AN: 5128

South Asian (SAS) AF: 0.0908 AC: 438 AN: 4824

European-Finnish (FIN) AF: 0.254 AC: 2641 AN: 10402

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.214 AC: 14468 AN: 67586

Other (OTH) AF: 0.171 AC: 360 AN: 2100

Alfa AF: 0.108 Hom.: 189

Bravo AF: 0.156

Asia WGS AF: 0.0650 AC: 222 AN: 3404

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	-0.78
CADD	Benign	6.5
DANN	Benign	0.59
PhyloP100		-0.15
PromoterAI		-0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=298/2	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3026433; hg19: chr12-110719192;