chr13-51950352-T-G

Variant names:

• chr13-51950352-T-G
• rs1061472
• NM_000053.4:c.2495A>C
• ATP7B p.Lys832Thr

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PP3_Moderate

The NM_000053.4(ATP7B):c.2495A>C (p.Lys832Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000124 (AC=2) in the gnomAD database across 1,613,778 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000299. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). 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.K832R: Benign (ClinVar VariationId 35707, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Predictors: REVEL: 0.89: Pathogenic
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19
• Publications: 35 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: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 10 pathogenic, 0 benign (OR vs. background: 105.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000299 — very rare for AR gene (base 0.001, raised to 0.00322 by highest known P/LP ClinVar AF 0.00322) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

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>C p.Lys832Thr	missense	Exon 10 of 21	Prot: NP_000044.2
	ATP7B NM_001406511.1		c.2495A>C p.Lys832Thr	missense	Exon 11 of 22	Prot: NP_001393440.1
	ATP7B NM_001406512.1		c.2495A>C p.Lys832Thr	missense	Exon 11 of 22	Prot: NP_001393441.1

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.2495A>Cp.Lys832Thr

Exon rankExon 10 of 21

missense

Prot: NP_000044.2

ATP7B NM_001406511.1

HGVSc / HGVSpc.2495A>Cp.Lys832Thr

Exon rankExon 11 of 22

missense

Prot: NP_001393440.1

ATP7B NM_001406512.1

HGVSc / HGVSpc.2495A>Cp.Lys832Thr

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>C p.Lys832Thr	missense	Exon 10 of 21	Prot: ENSP00000242839
	ATP7B ENST00000634844.2	TSL:1	c.2351A>C p.Lys784Thr	missense	Exon 10 of 21	Prot: ENSP00000489398
	ATP7B ENST00000418097.8	TSL:1	c.2495A>C p.Lys832Thr	missense	Exon 10 of 20	Prot: ENSP00000393343

ATP7B ENST00000242839.10

MANE Select

HGVSc / HGVSpc.2495A>Cp.Lys832Thr

Exon rankExon 10 of 21

missense

Prot: ENSP00000242839

ATP7B ENST00000634844.2

TSL:1

HGVSc / HGVSpc.2351A>Cp.Lys784Thr

Exon rankExon 10 of 21

missense

Prot: ENSP00000489398

ATP7B ENST00000418097.8

TSL:1

HGVSc / HGVSpc.2495A>Cp.Lys832Thr

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:151940	Cov:31
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461838	Cov:71
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:151940	Cov:31
TOPMed (Bravo) Warning	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:114166	AN:732664	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000238	1	41958	0.00	0	66886

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
FuncVEP CTI	Pathogenic	0.73
GPN-Star LLR	N/A	-8.4
GPN-Star score	N/A	8.4
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.87	D
Mutation Taster	N/A	7/93	disease causing
MutationAssessor	Uncertain	2.3	M
PhyloP100	Uncertain	6.2
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.1	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.92
VESM-3B	Benign	-12

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar