NM_004320.6:c.-22C>T

Variant names:

• chr16-28878650-C-T
• rs75273069
• NM_004320.6:c.-22C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004320.6(ATP2A1):​c.-22C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00983 in 1,572,948 control chromosomes in the GnomAD database, including 1,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (687 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (648 hom.)
• Consequence: ATP2A1 NM_004320.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.160
• Publications: 5 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-AS1 (HGNC:51370): (ATP2A1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 16-28878650-C-T is Benign according to our data. Variant chr16-28878650-C-T is described in ClinVar as [Benign]. Clinvar id is 318764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.-22C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_004320.6	c.-22C>T		5_prime_UTR_variant	Exon 1 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.-22C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 22		NP_775293.1
ATP2A1	NM_173201.5	c.-22C>T		5_prime_UTR_variant	Exon 1 of 22		NP_775293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.-22C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000395503.9	c.-22C>T		5_prime_UTR_variant	Exon 1 of 23	1	NM_004320.6	ENSP00000378879.5

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7803 AN: 152078 Hom.: 683 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0127 AC: 2505 AN: 198022 AF XY: 0.00903

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.00792

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000416

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00535 AC: 7607 AN: 1420752 Hom.: 648 Cov.: 29 AF XY: 0.00458 AC XY: 3228 AN XY: 704262

African (AFR) AF: 0.187 AC: 6119 AN: 32638

American (AMR) AF: 0.00936 AC: 367 AN: 39222

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25436

East Asian (EAS) AF: 0.00 AC: 0 AN: 38198

South Asian (SAS) AF: 0.000353 AC: 29 AN: 82240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50774

Middle Eastern (MID) AF: 0.00628 AC: 36 AN: 5728

European-Non Finnish (NFE) AF: 0.000276 AC: 300 AN: 1087650

Other (OTH) AF: 0.0128 AC: 755 AN: 58866

GnomAD4 genome AF: 0.0516 AC: 7850 AN: 152196 Hom.: 687 Cov.: 32 AF XY: 0.0506 AC XY: 3766 AN XY: 74430

African (AFR) AF: 0.179 AC: 7430 AN: 41474

American (AMR) AF: 0.0197 AC: 302 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68016

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0199 Hom.: 96

Bravo AF: 0.0599

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Brody myopathy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		-0.16
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=300/0	polymorphism (auto)

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: rs75273069; hg19: chr16-28889971; COSMIC: COSV59465766; COSMIC: COSV59465766;