NM_004320.6:c.1948G>A

Variant names:

• chr16-28900764-G-A
• rs74573581
• NM_004320.6:c.1948G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004320.6(ATP2A1):​c.1948G>A​(p.Asp650Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000897 in 1,614,192 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D650A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (5 hom.)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.47
• Publications: 3 publications found

Genes affected

ATP2A1 (HGNC:811): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Oct 2013]

ATP2A1 Gene-Disease associations (from GenCC):

• Brody myopathy

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008668274).
• BP6: Variant 16-28900764-G-A is Benign according to our data. Variant chr16-28900764-G-A is described in ClinVar as Benign. ClinVar VariationId is 387411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00471 (717/152314) while in subpopulation AFR AF = 0.0159 (660/41572). AF 95% confidence interval is 0.0149. There are 3 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004320.6. 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
	ATP2A1	NM_004320.6	MANE Select	c.1948G>A	p.Asp650Asn	missense	Exon 15 of 23	NP_004311.1
	ATP2A1	NM_173201.5		c.1948G>A	p.Asp650Asn	missense	Exon 15 of 22	NP_775293.1
	ATP2A1	NM_001286075.2		c.1573G>A	p.Asp525Asn	missense	Exon 13 of 21	NP_001273004.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1948G>A	p.Asp650Asn	missense	Exon 15 of 23	ENSP00000378879.5
	ATP2A1	ENST00000971328.1		c.1981G>A	p.Asp661Asn	missense	Exon 15 of 23	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.1948G>A	p.Asp650Asn	missense	Exon 15 of 22	ENSP00000349595.3

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152196 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00129 AC: 323 AN: 250284 AF XY: 0.000930

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000500 AC: 731 AN: 1461878 Hom.: 5 Cov.: 32 AF XY: 0.000422 AC XY: 307 AN XY: 727242

African (AFR) AF: 0.0168 AC: 564 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1112008

Other (OTH) AF: 0.00119 AC: 72 AN: 60396

GnomAD4 genome AF: 0.00471 AC: 717 AN: 152314 Hom.: 3 Cov.: 31 AF XY: 0.00459 AC XY: 342 AN XY: 74478

African (AFR) AF: 0.0159 AC: 660 AN: 41572

American (AMR) AF: 0.00288 AC: 44 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00111 Hom.: 7

Bravo AF: 0.00540

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0141 AC: 62

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00153 AC: 186

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Brody myopathy (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0087	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.53	N
PhyloP100		3.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.47	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.070	T
Polyphen		0.0	B
Vest4		0.35
MVP		0.97
MPC		0.43
ClinPred		0.019	T
GERP RS		4.3
Varity_R		0.073
gMVP		0.55
Mutation Taster		=99/1	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: rs74573581; hg19: chr16-28912085; COSMIC: COSV99050848; COSMIC: COSV99050848;