NM_170665.4:c.-10C>G

Variant names:

• chr12-110281780-C-G
• rs201929640
• NM_170665.4:c.-10C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_170665.4(ATP2A2):​c.-10C>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 0.00899 in 1,492,406 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (69 hom.)
• Consequence: ATP2A2 NM_170665.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.352
• 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), Illumina, Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-110281780-C-G is Benign according to our data. Variant chr12-110281780-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 307158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1045 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.-10C>G		5_prime_UTR	Exon 1 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413013.1		c.-10C>G		5_prime_UTR	Exon 1 of 19	NP_001399942.1
	ATP2A2	NM_001413014.1		c.-10C>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.-10C>G		5_prime_UTR	Exon 1 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.-10C>G		5_prime_UTR	Exon 1 of 21	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000943653.1		c.-10C>G		5_prime_UTR	Exon 2 of 21	ENSP00000613712.1

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 1046 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00943

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00752 AC: 884 AN: 117624 AF XY: 0.00719

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00172

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.00893

Gnomad OTH exome AF: 0.00799

GnomAD4 exome AF: 0.00923 AC: 12376 AN: 1340252 Hom.: 69 Cov.: 30 AF XY: 0.00910 AC XY: 6012 AN XY: 660728

African (AFR) AF: 0.000981 AC: 27 AN: 27526

American (AMR) AF: 0.00495 AC: 140 AN: 28276

Ashkenazi Jewish (ASJ) AF: 0.00135 AC: 31 AN: 23010

East Asian (EAS) AF: 0.00 AC: 0 AN: 30640

South Asian (SAS) AF: 0.00526 AC: 387 AN: 73618

European-Finnish (FIN) AF: 0.0178 AC: 846 AN: 47588

Middle Eastern (MID) AF: 0.00167 AC: 9 AN: 5402

European-Non Finnish (NFE) AF: 0.0101 AC: 10593 AN: 1049198

Other (OTH) AF: 0.00624 AC: 343 AN: 54994

GnomAD4 genome AF: 0.00687 AC: 1045 AN: 152154 Hom.: 1 Cov.: 32 AF XY: 0.00678 AC XY: 504 AN XY: 74372

African (AFR) AF: 0.00166 AC: 69 AN: 41530

American (AMR) AF: 0.00778 AC: 119 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4824

European-Finnish (FIN) AF: 0.0171 AC: 181 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00943 AC: 641 AN: 67966

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00627 Hom.: 2

Bravo AF: 0.00598

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Keratosis follicularis (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Acrokeratosis verruciformis of Hopf (1)
-	-	1	Keratosis follicularis;C0265971:Acrokeratosis verruciformis of Hopf (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.81
PhyloP100		0.35
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=299/1	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: rs201929640; hg19: chr12-110719585;