chr16-28878726-A-G

Position:

• chr16-28878726-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004320.6(ATP2A1):​c.55A>G​(p.Ser19Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP2A1 NM_004320.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62

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-AS1 (HGNC:51370): (ATP2A1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27608272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.55A>G	p.Ser19Gly	missense_variant	1/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.55A>G	p.Ser19Gly	missense_variant	1/22		NP_775293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.55A>G	p.Ser19Gly	missense_variant	1/23	1	NM_004320.6	ENSP00000378879	P4
ATP2A1-AS1	ENST00000691192.2	n.1211T>C		non_coding_transcript_exon_variant	1/1
ATP2A1	ENST00000357084.7	c.55A>G	p.Ser19Gly	missense_variant	1/22	2		ENSP00000349595	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Brody myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	0.052
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.58	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.061	T;T
Sift4G	Uncertain	0.047	D;D
Polyphen		0.0	B;B
Vest4		0.10
MutPred		0.48		Loss of glycosylation at S19 (P = 0.0587);Loss of glycosylation at S19 (P = 0.0587);
MVP		0.93
MPC		0.46
ClinPred		0.82	D
GERP RS		3.4
Varity_R		0.12
gMVP		0.28

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: rs1963351388; hg19: chr16-28890047;