NM_170665.4:c.327A>G

Variant names:

• chr12-110296601-A-G
• rs55984131
• NM_170665.4:c.327A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_170665.4(ATP2A2):​c.327A>G​(p.Glu109Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.009 in 1,614,132 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (73 hom.)
• Consequence: ATP2A2 NM_170665.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.31
• Publications: 5 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008938611).
• BP6: Variant 12-110296601-A-G is Benign according to our data. Variant chr12-110296601-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 307165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.31 with no splicing effect.
• BS2: High AC in GnomAd4 at 1043 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.327A>G	p.Glu109Glu	splice_region synonymous	Exon 5 of 20	NP_733765.1	P16615-1
	ATP2A2	NM_001413015.1		c.-49A>G		splice_region	Exon 5 of 20	NP_001399944.1
	ATP2A2	NM_001413013.1		c.222A>G	p.Glu74Glu	splice_region synonymous	Exon 4 of 19	NP_001399942.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A2	ENST00000539276.7	TSL:1 MANE Select	c.327A>G	p.Glu109Glu	splice_region synonymous	Exon 5 of 20	ENSP00000440045.2	P16615-1
	ATP2A2	ENST00000308664.10	TSL:1	c.327A>G	p.Glu109Glu	splice_region synonymous	Exon 5 of 21	ENSP00000311186.6	P16615-2
	ATP2A2	ENST00000552636.2	TSL:4	c.-49A>G		splice_region	Exon 5 of 5	ENSP00000447406.2	F8W1Z7

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1044 AN: 152208 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00749 AC: 1883 AN: 251390 AF XY: 0.00763

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.00934

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00922 AC: 13479 AN: 1461806 Hom.: 73 Cov.: 31 AF XY: 0.00913 AC XY: 6641 AN XY: 727204

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00512 AC: 229 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00559 AC: 482 AN: 86256

European-Finnish (FIN) AF: 0.0182 AC: 972 AN: 53418

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0102 AC: 11317 AN: 1111956

Other (OTH) AF: 0.00647 AC: 391 AN: 60392

GnomAD4 genome AF: 0.00685 AC: 1043 AN: 152326 Hom.: 1 Cov.: 31 AF XY: 0.00675 AC XY: 503 AN XY: 74490

African (AFR) AF: 0.00166 AC: 69 AN: 41574

American (AMR) AF: 0.00772 AC: 118 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4828

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00941 AC: 640 AN: 68032

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00782 Hom.: 12

Bravo AF: 0.00600

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00730 AC: 886

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00807

EpiControl AF: 0.00889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Keratosis follicularis (3)
-	-	3	not specified (3)
-	-	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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.87
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.82	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.70	T
PhyloP100		2.3
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.42
Vest4		0.18
MVP		0.84
ClinPred		0.042	T
GERP RS		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=61/39	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: rs55984131; hg19: chr12-110734406;