1-116384063-A-G

Position:

• chr1-116384063-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000701.8(ATP1A1):​c.62A>G​(p.Lys21Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A1 NM_000701.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

Genes affected

ATP1A1 (HGNC:799): (ATPase Na+/K+ transporting subunit alpha 1) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, 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 catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 1 subunit. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ATP1A1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue N6-acetyllysine (size 0) in uniprot entity AT1A1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A1. . Gene score misZ 6.2154 (greater than the threshold 3.09). Trascript score misZ 8.228 (greater than threshold 3.09). GenCC has associacion of gene with hypomagnesemia, seizures, and intellectual disability 2, charcot-marie-tooth disease, axonal, type 2DD.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20682934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A1	NM_000701.8	c.62A>G	p.Lys21Arg	missense_variant	2/23	ENST00000295598.10	NP_000692.2
ATP1A1	NM_001160233.2	c.62A>G	p.Lys21Arg	missense_variant	2/23		NP_001153705.1
ATP1A1	NM_001160234.2	c.-32A>G		5_prime_UTR_variant	2/23		NP_001153706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A1	ENST00000295598.10	c.62A>G	p.Lys21Arg	missense_variant	2/23	1	NM_000701.8	ENSP00000295598.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP1A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with ATP1A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 21 of the ATP1A1 protein (p.Lys21Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.72	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.19	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0	B;.
Vest4		0.27
MutPred		0.25		Loss of ubiquitination at K21 (P = 0.0233);Loss of ubiquitination at K21 (P = 0.0233);
MVP		0.89
MPC		1.1
ClinPred		0.67	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-116926685;