rs2217342

Variant names:

• chr19-41985364-A-C
• rs2217342
• NM_152296.5:c.666T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-41985364-A-C
• chr19-41985364-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256214.2(ATP1A3):​c.705T>G​(p.Thr235Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 1,614,130 control chromosomes in the GnomAD database, including 660,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T235T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.92 (64869 hom., cov: 33)
  • Exomes 𝑓: 0.90 (595802 hom.)
• Consequence: ATP1A3 NM_001256214.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -4.07
• Publications: 38 publications found

Genes affected

ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) 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 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ATP1A3 Gene-Disease associations (from GenCC):

• alternating hemiplegia of childhood 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ATP1A3-associated neurological disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• developmental and epileptic encephalopathy 99

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• dystonia 12

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• encephalopathy, acute, infection-induced

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• alternating hemiplegia of childhood

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000285505 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 19-41985364-A-C is Benign according to our data. Variant chr19-41985364-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256214.2. 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
	ATP1A3	NM_152296.5	MANE Select	c.666T>G	p.Thr222Thr	synonymous	Exon 7 of 23	NP_689509.1
	ATP1A3	NM_001256214.2		c.705T>G	p.Thr235Thr	synonymous	Exon 7 of 23	NP_001243143.1
	ATP1A3	NM_001256213.2		c.699T>G	p.Thr233Thr	synonymous	Exon 7 of 23	NP_001243142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.666T>G	p.Thr222Thr	synonymous	Exon 7 of 23	ENSP00000498113.1
	ENSG00000285505	ENST00000644613.1		n.666T>G		non_coding_transcript_exon	Exon 7 of 25	ENSP00000494711.1
	ATP1A3	ENST00000545399.6	TSL:2	c.705T>G	p.Thr235Thr	synonymous	Exon 7 of 23	ENSP00000444688.1

Frequencies

GnomAD3 genomes AF: 0.922 AC: 140238 AN: 152138 Hom.: 64804 Cov.: 33

Gnomad AFR AF: 0.981

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.942

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.887

GnomAD2 exomes AF: 0.890 AC: 223667 AN: 251436 AF XY: 0.885

Gnomad AFR exome AF: 0.985

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.865

Gnomad EAS exome AF: 0.870

Gnomad FIN exome AF: 0.938

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.886

GnomAD4 exome AF: 0.902 AC: 1318948 AN: 1461874 Hom.: 595802 Cov.: 79 AF XY: 0.899 AC XY: 653920 AN XY: 727238

African (AFR) AF: 0.984 AC: 32954 AN: 33480

American (AMR) AF: 0.858 AC: 38355 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 22553 AN: 26136

East Asian (EAS) AF: 0.878 AC: 34853 AN: 39700

South Asian (SAS) AF: 0.819 AC: 70658 AN: 86256

European-Finnish (FIN) AF: 0.939 AC: 50158 AN: 53420

Middle Eastern (MID) AF: 0.795 AC: 4587 AN: 5768

European-Non Finnish (NFE) AF: 0.909 AC: 1010704 AN: 1111996

Other (OTH) AF: 0.896 AC: 54126 AN: 60394

GnomAD4 genome AF: 0.922 AC: 140367 AN: 152256 Hom.: 64869 Cov.: 33 AF XY: 0.921 AC XY: 68525 AN XY: 74438

African (AFR) AF: 0.981 AC: 40758 AN: 41550

American (AMR) AF: 0.883 AC: 13502 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 2995 AN: 3472

East Asian (EAS) AF: 0.875 AC: 4528 AN: 5172

South Asian (SAS) AF: 0.822 AC: 3970 AN: 4828

European-Finnish (FIN) AF: 0.942 AC: 10000 AN: 10618

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61653 AN: 68006

Other (OTH) AF: 0.889 AC: 1878 AN: 2112

Alfa AF: 0.903 Hom.: 103293

Bravo AF: 0.920

EpiCase AF: 0.894

EpiControl AF: 0.897

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Dystonia 12 (3)
-	-	3	not provided (3)
-	-	2	Alternating hemiplegia of childhood 2 (2)
-	-	1	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.012
DANN	Benign	0.19
PhyloP100		-4.1
Mutation Taster		=99/1	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: rs2217342; hg19: chr19-42489516; COSMIC: COSV57488667; COSMIC: COSV57488667;