1-169130042-A-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001677.4(ATP1B1):c.600A>C(p.Pro200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00865 in 1,614,048 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (91 hom.)
• Consequence: ATP1B1 NM_001677.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93

Genes affected

ATP1B1 (HGNC:804): (ATPase Na+/K+ transporting subunit beta 1) The protein encoded by this gene belongs to the family of Na+/K+ and H+/K+ ATPases beta chain proteins, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane. The glycoprotein subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes a beta 1 subunit. Alternatively spliced transcript variants encoding different isoforms have been described, but their biological validity is not known. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-169130042-A-C is Benign according to our data. Variant chr1-169130042-A-C is described in ClinVar as [Benign]. Clinvar id is 496144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS2: High AC in GnomAd at 869 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1B1	NM_001677.4	c.600A>C	p.Pro200=	synonymous_variant	5/6	ENST00000367815.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1B1	ENST00000367815.9	c.600A>C	p.Pro200=	synonymous_variant	5/6	1	NM_001677.4	P1

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 869 AN: 152198 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00998

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00627 AC: 1576 AN: 251418 Hom.: 9 AF XY: 0.00671 AC XY: 912 AN XY: 135880

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00578

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.00962

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00896 AC: 13091 AN: 1461732 Hom.: 91 Cov.: 31 AF XY: 0.00888 AC XY: 6459 AN XY: 727158

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00547

Gnomad4 FIN exome AF: 0.00346

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00802

GnomAD4 genome AF: 0.00570 AC: 868 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00494 AC XY: 368 AN XY: 74488

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00997

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00799 Hom.: 3

Bravo AF: 0.00538

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.00978

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2017	Variant summary: The ATP1B1 c.600A>C (p.Pro200Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a benign outcome for this variant along with 5/5 splice prediction tools predicting the variant not to have an impact on normal splicing. This variant was found in 830/121356 control chromosomes (6 homozygotes) at a frequency of 0.0068394, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic ATP1B1 variant (0.00001), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.35
Dann	Benign	0.65

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: rs61803314; hg19: chr1-169099280;