16-28894226-C-T

Position:

• chr16-28894226-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004320.6(ATP2A1):​c.1167C>T​(p.Tyr389Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,613,960 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (13 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -2.64

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 16-28894226-C-T is Benign according to our data. Variant chr16-28894226-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384410.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-2.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00254 (386/152214) while in subpopulation NFE AF= 0.00368 (250/68010). AF 95% confidence interval is 0.0033. There are 2 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1167C>T	p.Tyr389Tyr	synonymous_variant	10/23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1167C>T	p.Tyr389Tyr	synonymous_variant	10/22		NP_775293.1
ATP2A1	NM_001286075.2	c.792C>T	p.Tyr264Tyr	synonymous_variant	8/21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1167C>T	p.Tyr389Tyr	synonymous_variant	10/23	1	NM_004320.6	ENSP00000378879.5

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152096 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00285 AC: 716 AN: 251106 Hom.: 2 AF XY: 0.00274 AC XY: 372 AN XY: 135710

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00586

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00337

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00331 AC: 4844 AN: 1461746 Hom.: 13 Cov.: 32 AF XY: 0.00320 AC XY: 2324 AN XY: 727164

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.00362

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.00254 AC: 386 AN: 152214 Hom.: 2 Cov.: 31 AF XY: 0.00224 AC XY: 167 AN XY: 74418

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00369 Hom.: 0

Bravo AF: 0.00257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brody myopathy Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2020

- -

ATP2A1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.17
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41292388; hg19: chr16-28905547; COSMIC: COSV63921465; COSMIC: COSV63921465;