NM_000053.4:c.2495A>G

Variant names:

• chr13-51950352-T-C
• rs1061472
• NM_000053.4:c.2495A>G
• ATP7B p.Lys832Arg

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP6_Strong

The NM_000053.4(ATP7B):c.2495A>G (p.Lys832Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.562 (AC=907,251) in the gnomAD database across 1,613,790 control chromosomes, including 256,999 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.608. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K832= (synonymous): Likely_benign (ClinVar VariationId 1652777, 1 star); p.K832R: Likely_benign (ClinVar VariationId 1122352, 1 star); p.K832T: Uncertain_significance (ClinVar VariationId 2266434, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.54 (22333 hom., cov: 31)
  • Exomes 𝑓: 0.56 (234666 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Predictors: REVEL: 0.47: Uncertain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:22
• Conservation: PhyloP100: 6.19
• Publications: 107 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: Labcorp Genetics (formerly Invitae), Natera, ClinGen, Genomics England PanelApp, Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (22/23 total B/LB).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6080 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated classification 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	Prot: NP_000044.2
	ATP7B NM_001406511.1		c.2495A>G p.Lys832Arg	missense	Exon 11 of 22	Prot: NP_001393440.1
	ATP7B NM_001406512.1		c.2495A>G p.Lys832Arg	missense	Exon 11 of 22	Prot: NP_001393441.1

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.2495A>Gp.Lys832Arg

Exon rankExon 10 of 21

missense

Prot: NP_000044.2

ATP7B NM_001406511.1

HGVSc / HGVSpc.2495A>Gp.Lys832Arg

Exon rankExon 11 of 22

missense

Prot: NP_001393440.1

ATP7B NM_001406512.1

HGVSc / HGVSpc.2495A>Gp.Lys832Arg

Exon rankExon 11 of 22

missense

Prot: NP_001393441.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATP7B ENST00000242839.10	MANE Select	c.2495A>G p.Lys832Arg	missense	Exon 10 of 21	Prot: ENSP00000242839
	ATP7B ENST00000634844.2	TSL:1	c.2351A>G p.Lys784Arg	missense	Exon 10 of 21	Prot: ENSP00000489398
	ATP7B ENST00000418097.8	TSL:1	c.2495A>G p.Lys832Arg	missense	Exon 10 of 20	Prot: ENSP00000393343

ATP7B ENST00000242839.10

MANE Select

HGVSc / HGVSpc.2495A>Gp.Lys832Arg

Exon rankExon 10 of 21

missense

Prot: ENSP00000242839

ATP7B ENST00000634844.2

TSL:1

HGVSc / HGVSpc.2351A>Gp.Lys784Arg

Exon rankExon 10 of 21

missense

Prot: ENSP00000489398

ATP7B ENST00000418097.8

TSL:1

HGVSc / HGVSpc.2495A>Gp.Lys832Arg

Exon rankExon 10 of 20

missense

Prot: ENSP00000393343

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.540	AC:81944	Hom:22328	AN:151884	Cov:31
GnomAD2 exomes	AF: 0.539	AC:134395	Hom:	AN:249370	Cov:
GnomAD4 exome	AF: 0.565	AC:825260	Hom:234666	AN:1461788	Cov:71
GnomAD4 genome	AF: 0.539	AC:81991	Hom:22333	AN:152002	Cov:31
TOPMed (Bravo)	AF: 0.532	AC:140701	Hom:37761	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.556	AC:407594	Hom:114166	AN:732664	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.554	AC:1297	Hom:359	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.419	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.547	AC:164	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.552	AC:7028	Hom:	AN:12728	Cov:
GenomeAsia100K	AF: 0.504	AC:1750	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.400	AC:2894	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.682	AC:120	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.405	AC:49677	Hom:10133	AN:122660	Cov:
Turkish Variome	AF: 0.591	AC:3969	Hom:1215	AN:6720	Cov:
UK10K	AF: 0.578	AC:4374	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.413	AC:3702	Hom:763	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.556 *	6165	11090	0.562 *	9894	17590
BipEx(Bipolar disorder (including schizoaffective))	0.576	16358	28420	0.568	16395	28844
Epi25(Epilepsy)	0.558	23401	41958	0.558	37301	66880
SCHEMA(Schizophrenia)	0.507	75088	148054	0.512	123040	240304

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	Wilson disease (11)
-	-	9	not specified (9)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
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
GPN-Star LLR	N/A	-6.1
GPN-Star score	N/A	6.1
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.93	T
Mutation Taster	N/A	46/54	polymorphism (auto)
MutationAssessor	Benign	0.41	N
PhyloP100	Uncertain	6.2
popEVE	Benign	-3.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.47
Sift	Benign	0.087	T
Sift4G	Benign	0.12	T
Varity_R	N/A	0.34
VESM-3B	Benign	-6.4

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1061472;

hg19: chr13-52524488;

COSMIC: COSV54438485;

COSMIC: COSV54438485;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar