chr1-160115874-G-T

Variant names:

• chr1-160115874-G-T
• rs1421966486
• NM_000702.4:c.12+1G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000702.4(ATP1A2):​c.12+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP1A2 NM_000702.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.50

Genes affected

ATP1A2 (HGNC:800): (ATPase Na+/K+ transporting subunit alpha 2) 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 2 subunit. Mutations in this gene result in familial basilar or hemiplegic migraines, and in a rare syndrome known as alternating hemiplegia of childhood. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.1, offset of 38, new splice context is: aggGTgagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP1A2	NM_000702.4	c.12+1G>T		splice_donor_variant, intron_variant	Intron 1 of 22	ENST00000361216.8	NP_000693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A2	ENST00000361216.8	c.12+1G>T		splice_donor_variant, intron_variant	Intron 1 of 22	1	NM_000702.4	ENSP00000354490.3
ATP1A2	ENST00000392233.7	c.12+1G>T		splice_donor_variant, intron_variant	Intron 1 of 22	5		ENSP00000376066.3
ATP1A2	ENST00000472488.5	n.115+1G>T		splice_donor_variant, intron_variant	Intron 1 of 19	2
ATP1A2	ENST00000478587.1	n.111+1G>T		splice_donor_variant, intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449472 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.92	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 37
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1421966486; hg19: chr1-160085664;