rs2139229895

Variant names:

• chr13-51950351-CT-TC
• rs2139229895
• NM_000053.4:c.2495_2496delinsGA
• ATP7B p.Lys832Arg

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM1PM2BP6_Moderate

The NM_000053.4(ATP7B):c.2495_2496delinsGA (p.Lys832Arg) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: Benign (ClinVar VariationId 35707, 2 stars); 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: not found (cov: 31)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.19
• Publications: 0 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: Uncertain_significance. The variant received 2 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		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (base 0.001, raised to 0.00322 by highest known P/LP ClinVar AF 0.00322) — PM2 moderate.
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

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.2495_2496delinsGA p.Lys832Arg	missense	Exon 10 of 21	Prot: NP_000044.2
	ATP7B NM_001406511.1		c.2495_2496delinsGA p.Lys832Arg	missense	Exon 11 of 22	Prot: NP_001393440.1
	ATP7B NM_001406512.1		c.2495_2496delinsGA p.Lys832Arg	missense	Exon 11 of 22	Prot: NP_001393441.1

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.2495_2496delinsGAp.Lys832Arg

Exon rankExon 10 of 21

missense

Prot: NP_000044.2

ATP7B NM_001406511.1

HGVSc / HGVSpc.2495_2496delinsGAp.Lys832Arg

Exon rankExon 11 of 22

missense

Prot: NP_001393440.1

ATP7B NM_001406512.1

HGVSc / HGVSpc.2495_2496delinsGAp.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.2495_2496delinsGA p.Lys832Arg	missense	Exon 10 of 21	Prot: ENSP00000242839
	ATP7B ENST00000634844.2	TSL:1	c.2351_2352delinsGA p.Lys784Arg	missense	Exon 10 of 21	Prot: ENSP00000489398
	ATP7B ENST00000418097.8	TSL:1	c.2495_2496delinsGA p.Lys832Arg	missense	Exon 10 of 20	Prot: ENSP00000393343

ATP7B ENST00000242839.10

MANE Select

HGVSc / HGVSpc.2495_2496delinsGAp.Lys832Arg

Exon rankExon 10 of 21

missense

Prot: ENSP00000242839

ATP7B ENST00000634844.2

TSL:1

HGVSc / HGVSpc.2351_2352delinsGAp.Lys784Arg

Exon rankExon 10 of 21

missense

Prot: ENSP00000489398

ATP7B ENST00000418097.8

TSL:1

HGVSc / HGVSpc.2495_2496delinsGAp.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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Wilson disease (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	6.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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: rs2139229895;

hg19: chr13-52524487;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar