NM_000053.4:c.2495A>G

Variant names:

• chr13-51950352-T-C
• rs1061472
• NM_000053.4:c.2495A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.2495A>G​(p.Lys832Arg) variant causes a missense change. The variant allele was found at a frequency of 0.562 in 1,613,790 control chromosomes in the GnomAD database, including 256,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K832T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.54 (22333 hom., cov: 31)
  • Exomes 𝑓: 0.56 (234666 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:20
• Conservation: PhyloP100: 6.19
• Publications: 104 publications found

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000053.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037171245).
• BP6: Variant 13-51950352-T-C is Benign according to our data. Variant chr13-51950352-T-C is described in ClinVar as Benign. ClinVar VariationId is 35707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. 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
	ATP7B	NM_000053.4	MANE Select	c.2495A>G	p.Lys832Arg	missense	Exon 10 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2495A>G	p.Lys832Arg	missense	Exon 11 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2495A>G	p.Lys832Arg	missense	Exon 11 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2495A>G	p.Lys832Arg	missense	Exon 10 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2351A>G	p.Lys784Arg	missense	Exon 10 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.2495A>G	p.Lys832Arg	missense	Exon 10 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81944 AN: 151884 Hom.: 22328 Cov.: 31

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.565

GnomAD2 exomes AF: 0.539 AC: 134395 AN: 249370 AF XY: 0.542

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.491

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.574

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.565 AC: 825260 AN: 1461788 Hom.: 234666 Cov.: 71 AF XY: 0.564 AC XY: 409857 AN XY: 727186

African (AFR) AF: 0.495 AC: 16569 AN: 33480

American (AMR) AF: 0.496 AC: 22190 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14862 AN: 26136

East Asian (EAS) AF: 0.401 AC: 15921 AN: 39694

South Asian (SAS) AF: 0.509 AC: 43871 AN: 86254

European-Finnish (FIN) AF: 0.602 AC: 32166 AN: 53394

Middle Eastern (MID) AF: 0.625 AC: 3605 AN: 5768

European-Non Finnish (NFE) AF: 0.578 AC: 642183 AN: 1111956

Other (OTH) AF: 0.561 AC: 33893 AN: 60394

GnomAD4 genome AF: 0.539 AC: 81991 AN: 152002 Hom.: 22333 Cov.: 31 AF XY: 0.538 AC XY: 39989 AN XY: 74290

African (AFR) AF: 0.493 AC: 20424 AN: 41444

American (AMR) AF: 0.507 AC: 7744 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1959 AN: 3470

East Asian (EAS) AF: 0.405 AC: 2089 AN: 5162

South Asian (SAS) AF: 0.515 AC: 2480 AN: 4818

European-Finnish (FIN) AF: 0.599 AC: 6327 AN: 10558

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39221 AN: 67950

Other (OTH) AF: 0.566 AC: 1195 AN: 2110

Alfa AF: 0.558 Hom.: 107634

Bravo AF: 0.532

TwinsUK AF: 0.575 AC: 2132

ALSPAC AF: 0.582 AC: 2242

ESP6500AA AF: 0.484 AC: 2050

ESP6500EA AF: 0.586 AC: 4978

ExAC AF: 0.537 AC: 65059

Asia WGS AF: 0.504 AC: 1750 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.582

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	Wilson disease (11)
-	-	7	not specified (7)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.41	N
PhyloP100		6.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.47
Sift	Benign	0.087	T
Sift4G	Benign	0.12	T
Polyphen		0.42	B
Vest4		0.34
MPC		0.087
ClinPred		0.0087	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.79
Mutation Taster		=46/54	polymorphism (auto)

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: rs1061472; hg19: chr13-52524488; COSMIC: COSV54438485; COSMIC: COSV54438485;