16-28900790-C-T

Variant names:

• chr16-28900790-C-T
• rs61626938
• NM_004320.6:c.1974C>T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_004320.6(ATP2A1):​c.1974C>T​(p.Phe658Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: ATP2A1 NM_004320.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.81

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 -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-28900790-C-T is Benign according to our data. Variant chr16-28900790-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 388060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00275 (419/152302) while in subpopulation AFR AF= 0.00969 (403/41570). AF 95% confidence interval is 0.00891. There are 0 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP2A1	NM_004320.6	c.1974C>T	p.Phe658Phe	synonymous_variant	Exon 15 of 23	ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.1974C>T	p.Phe658Phe	synonymous_variant	Exon 15 of 22		NP_775293.1
ATP2A1	NM_001286075.2	c.1599C>T	p.Phe533Phe	synonymous_variant	Exon 13 of 21		NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP2A1	ENST00000395503.9	c.1974C>T	p.Phe658Phe	synonymous_variant	Exon 15 of 23	1	NM_004320.6	ENSP00000378879.5
ATP2A1	ENST00000357084.7	c.1974C>T	p.Phe658Phe	synonymous_variant	Exon 15 of 22	2		ENSP00000349595.3
ATP2A1	ENST00000536376.5	c.1599C>T	p.Phe533Phe	synonymous_variant	Exon 13 of 21	2		ENSP00000443101.1
ATP2A1	ENST00000564732.1	n.*617C>T		downstream_gene_variant		5		ENSP00000457357.1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000741 AC: 185 AN: 249732 Hom.: 0 AF XY: 0.000503 AC XY: 68 AN XY: 135178

Gnomad AFR exome AF: 0.00997

Gnomad AMR exome AF: 0.000405

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: 0.0000625

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000293 AC: 429 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.000254 AC XY: 185 AN XY: 727238

Gnomad4 AFR exome AF: 0.00974

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152302 Hom.: 0 Cov.: 31 AF XY: 0.00262 AC XY: 195 AN XY: 74470

Gnomad4 AFR AF: 0.00969

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000919 Hom.: 0

Bravo AF: 0.00322

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 31, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brody myopathy Benign:1

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.63
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61626938; hg19: chr16-28912111; COSMIC: COSV105253066; COSMIC: COSV105253066;