chr13-25579812-G-T

Variant names:

• chr13-25579812-G-T
• rs201822155
• NM_016529.6:c.1872G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016529.6(ATP8A2):​c.1872G>T​(p.Leu624Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP8A2 NM_016529.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.11
• Publications: 8 publications found

Genes affected

ATP8A2 (HGNC:13533): (ATPase phospholipid transporting 8A2) The protein encoded by this gene is a member of the P4 ATPase family of proteins, which are thought to be involved in a process called lipid flipping, whereby phospholipids are translocated inwards from the exoplasmic leaflet to the cytosolic leaflet of the cell membrane, which aids in generating and maintaining asymmetry in membrane lipids. This protein is predicted to contain an E1 E2 ATPase, a haloacid dehalogenase-like hydrolase (HAD) domain, and multiple transmembrane domains. Associations between this protein and cell cycle control protein 50A are important for translocation of phosphatidylserine across membranes. Mutations in this gene have been associated with a syndrome (CAMRQ4) characterized by cerebellar ataxia and cognitive disabilities. In addition, a translocation breakpoint within this gene was observed in an individual with neurological dysfunction. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

ATP8A2 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01633048).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016529.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	NM_016529.6	MANE Select	c.1872G>T	p.Leu624Phe	missense	Exon 22 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.1872G>T	p.Leu624Phe	missense	Exon 22 of 36	NP_001397934.1
	ATP8A2	NM_001313741.1		c.1752G>T	p.Leu584Phe	missense	Exon 22 of 36	NP_001300670.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.1872G>T	p.Leu624Phe	missense	Exon 22 of 37	ENSP00000371070.2
	ATP8A2	ENST00000281620.11	TSL:1	n.*1499G>T		non_coding_transcript_exon	Exon 22 of 38	ENSP00000281620.7
	ATP8A2	ENST00000491840.1	TSL:1	n.623G>T		non_coding_transcript_exon	Exon 7 of 20

Frequencies

GnomAD3 genomes AF: 0.0000927 AC: 14 AN: 150966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000875

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000164

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0357 AC: 5961 AN: 166820 AF XY: 0.0410

Gnomad AFR exome AF: 0.0362

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.0281

Gnomad FIN exome AF: 0.0392

Gnomad NFE exome AF: 0.0372

Gnomad OTH exome AF: 0.0210

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00525 AC: 7299 AN: 1391102 Hom.: 0 Cov.: 31 AF XY: 0.00661 AC XY: 4532 AN XY: 685668

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00604 AC: 192 AN: 31800

American (AMR) AF: 0.0188 AC: 676 AN: 35972

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 447 AN: 23448

East Asian (EAS) AF: 0.00955 AC: 348 AN: 36430

South Asian (SAS) AF: 0.0230 AC: 1722 AN: 75016

European-Finnish (FIN) AF: 0.0138 AC: 580 AN: 41892

Middle Eastern (MID) AF: 0.0408 AC: 180 AN: 4414

European-Non Finnish (NFE) AF: 0.00270 AC: 2925 AN: 1083986

Other (OTH) AF: 0.00394 AC: 229 AN: 58144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000927 AC: 14 AN: 150966 Hom.: 0 Cov.: 32 AF XY: 0.0000951 AC XY: 7 AN XY: 73588

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.000875 AC: 3 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67196

Other (OTH) AF: 0.00 AC: 0 AN: 2066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000171 Hom.: 0

ExAC AF: 0.0215 AC: 2538

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.25	D
PhyloP100		2.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.026	D
Vest4		0.87
MPC		1.5
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.35
gMVP		0.81
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201822155; hg19: chr13-26153950; COSMIC: COSV54935245;