chr16-28900764-G-T

Position:

• chr16-28900764-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004320.6(ATP2A1):​c.1948G>T​(p.Asp650Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1948G>T	p.Asp650Tyr	missense_variant	15/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1948G>T	p.Asp650Tyr	missense_variant	15/22		NP_775293.1
ATP2A1	NM_001286075.2	c.1573G>T	p.Asp525Tyr	missense_variant	13/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1948G>T	p.Asp650Tyr	missense_variant	15/23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.1948G>T	p.Asp650Tyr	missense_variant	15/22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.1573G>T	p.Asp525Tyr	missense_variant	13/21	2		ENSP00000443101.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250284 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.070	B;B;.
Vest4		0.44
MutPred		0.63		Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);.;
MVP		0.97
MPC		1.0
ClinPred		0.79	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs74573581; hg19: chr16-28912085;