chr13-25469044-A-C

Variant names:

• chr13-25469044-A-C
• rs7317185
• NM_016529.6:c.144A>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_016529.6(ATP8A2):​c.144A>C​(p.Gly48Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,613,836 control chromosomes in the GnomAD database, including 37,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4203 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33361 hom.)
• Consequence: ATP8A2 NM_016529.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.18
• Publications: 13 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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.141).
• BP6: Variant 13-25469044-A-C is Benign according to our data. Variant chr13-25469044-A-C is described in ClinVar as Benign. ClinVar VariationId is 128488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	NM_016529.6	MANE Select	c.144A>C	p.Gly48Gly	synonymous	Exon 2 of 37	NP_057613.4
	ATP8A2	NM_001411005.1		c.144A>C	p.Gly48Gly	synonymous	Exon 2 of 36	NP_001397934.1	A0A804HKW9
	ATP8A2	NM_001313741.1		c.24A>C	p.Gly8Gly	synonymous	Exon 2 of 36	NP_001300670.1	Q9NTI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP8A2	ENST00000381655.7	TSL:1 MANE Select	c.144A>C	p.Gly48Gly	synonymous	Exon 2 of 37	ENSP00000371070.2	Q9NTI2-4
	ATP8A2	ENST00000281620.11	TSL:1	n.144A>C		non_coding_transcript_exon	Exon 2 of 38	ENSP00000281620.7	F8W9B3
	ATP8A2	ENST00000682472.1		c.144A>C	p.Gly48Gly	synonymous	Exon 2 of 36	ENSP00000508103.1	A0A804HKW9

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34414 AN: 152058 Hom.: 4188 Cov.: 33

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.186 AC: 46331 AN: 249296 AF XY: 0.185

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.0907

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.210 AC: 307205 AN: 1461662 Hom.: 33361 Cov.: 34 AF XY: 0.208 AC XY: 151457 AN XY: 727140

African (AFR) AF: 0.311 AC: 10409 AN: 33476

American (AMR) AF: 0.126 AC: 5627 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 4071 AN: 26126

East Asian (EAS) AF: 0.124 AC: 4910 AN: 39690

South Asian (SAS) AF: 0.146 AC: 12570 AN: 86258

European-Finnish (FIN) AF: 0.198 AC: 10565 AN: 53404

Middle Eastern (MID) AF: 0.160 AC: 922 AN: 5768

European-Non Finnish (NFE) AF: 0.221 AC: 246133 AN: 1111842

Other (OTH) AF: 0.199 AC: 11998 AN: 60378

GnomAD4 genome AF: 0.227 AC: 34473 AN: 152174 Hom.: 4203 Cov.: 33 AF XY: 0.221 AC XY: 16463 AN XY: 74394

African (AFR) AF: 0.310 AC: 12859 AN: 41500

American (AMR) AF: 0.143 AC: 2190 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 550 AN: 3468

East Asian (EAS) AF: 0.109 AC: 561 AN: 5168

South Asian (SAS) AF: 0.140 AC: 674 AN: 4822

European-Finnish (FIN) AF: 0.193 AC: 2050 AN: 10606

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.221 AC: 14999 AN: 67982

Other (OTH) AF: 0.188 AC: 397 AN: 2116

Alfa AF: 0.218 Hom.: 14679

Bravo AF: 0.224

Asia WGS AF: 0.151 AC: 524 AN: 3478

EpiCase AF: 0.205

EpiControl AF: 0.211

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		1.2
PromoterAI		0.041	Neutral
Mutation Taster		=100/0	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: rs7317185; hg19: chr13-26043182; COSMIC: COSV54943308;