NM_004320.6:c.1764+6delC

Variant names:

• chr16-28898456-GC-G
• rs66716803
• NM_004320.6:c.1764+6delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004320.6(ATP2A1):​c.1764+6delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,612,294 control chromosomes in the GnomAD database, including 1,955 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (849 hom., cov: 31)
  • Exomes 𝑓: 0.014 (1106 hom.)
• Consequence: ATP2A1 NM_004320.6 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.108
• Publications: 4 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 Gene-Disease associations (from GenCC):

• Brody myopathy

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 16-28898456-GC-G is Benign according to our data. Variant chr16-28898456-GC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004320.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	NM_004320.6	MANE Select	c.1764+6delC		splice_region intron	N/A	NP_004311.1	O14983-2
	ATP2A1	NM_173201.5		c.1764+6delC		splice_region intron	N/A	NP_775293.1	O14983-1
	ATP2A1	NM_001286075.2		c.1389+6delC		splice_region intron	N/A	NP_001273004.1	O14983-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2A1	ENST00000395503.9	TSL:1 MANE Select	c.1764+6delC		splice_region intron	N/A	ENSP00000378879.5	O14983-2
	ATP2A1	ENST00000971328.1		c.1797+6delC		splice_region intron	N/A	ENSP00000641387.1
	ATP2A1	ENST00000357084.7	TSL:2	c.1764+6delC		splice_region intron	N/A	ENSP00000349595.3	O14983-1

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9692 AN: 152158 Hom.: 848 Cov.: 31

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.0425

GnomAD2 exomes AF: 0.0312 AC: 7554 AN: 242494 AF XY: 0.0258

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00780

Gnomad EAS exome AF: 0.151

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.00597

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0137 AC: 19997 AN: 1460018 Hom.: 1106 Cov.: 31 AF XY: 0.0128 AC XY: 9302 AN XY: 726260

African (AFR) AF: 0.195 AC: 6520 AN: 33440

American (AMR) AF: 0.0169 AC: 751 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 196 AN: 26094

East Asian (EAS) AF: 0.116 AC: 4613 AN: 39622

South Asian (SAS) AF: 0.00309 AC: 266 AN: 86128

European-Finnish (FIN) AF: 0.0181 AC: 958 AN: 52956

Middle Eastern (MID) AF: 0.0208 AC: 120 AN: 5756

European-Non Finnish (NFE) AF: 0.00437 AC: 4856 AN: 1111314

Other (OTH) AF: 0.0285 AC: 1717 AN: 60272

GnomAD4 genome AF: 0.0638 AC: 9711 AN: 152276 Hom.: 849 Cov.: 31 AF XY: 0.0622 AC XY: 4629 AN XY: 74464

African (AFR) AF: 0.190 AC: 7881 AN: 41538

American (AMR) AF: 0.0232 AC: 354 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.147 AC: 758 AN: 5160

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.0170 AC: 181 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00613 AC: 417 AN: 68036

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.00761 Hom.: 8

Bravo AF: 0.0702

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Brody myopathy (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.11
Mutation Taster		=90/10	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: rs66716803; hg19: chr16-28909777; COSMIC: COSV107451984; COSMIC: COSV107451984;