chr13-51958361-T-TG

Variant names:

• chr13-51958361-T-TG
• rs137853287
• NM_000053.4:c.2304dupC

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 18 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PM2PP5_Strong

The NM_000053.4(ATP7B):c.2304dupC (p.Met769HisfsTer26) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000979 (AC=158) in the gnomAD database across 1,614,022 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000112. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000694419: One functional study showed more than 50% decrease in ATPase activity in lymphoblasts a WD homozygote patient (Shah_AJHG_1997)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: ATP7B NM_000053.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 O:1
• Conservation: PhyloP100: -2.18
• Publications: 1 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: Genomics England PanelApp, ClinGen, Orphanet, Natera, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 8 of 21) at amino acid 768 of 1465, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~793 amino acids (672 amino acids lost).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000694419: One functional study showed more than 50% decrease in ATPase activity in lymphoblasts a WD homozygote patient (Shah_AJHG_1997).; SCV004845542: "Lymphoblast cells derived from an individual homozygous for this variant showed loss of copper-stimulated ATPase activity (PMID: 9311736)."; SCV005061166: An experimental study showed this variant caused a more than 50% decrease in ATPase activity in lymphoblasts in a homozygote patient affected with Wilson disease (Shah et al., 1997).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000112 — very rare for AR gene (base 0.001, raised to 0.00322 by highest known P/LP ClinVar AF 0.00322) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (29/29 total P/LP).

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.2304dupC p.Met769HisfsTer26	frameshift	Exon 8 of 21	Prot: NP_000044.2 UniProt:
	ATP7B NM_001406511.1		c.2304dupC p.Met769HisfsTer26	frameshift	Exon 9 of 22	Prot: NP_001393440.1 UniProt:
	ATP7B NM_001406512.1		c.2304dupC p.Met769HisfsTer26	frameshift	Exon 9 of 22	Prot: NP_001393441.1 UniProt:

ATP7B NM_000053.4

MANE Select

HGVSc / HGVSpc.2304dupCp.Met769HisfsTer26

Exon rankExon 8 of 21

frameshift

Prot: NP_000044.2UniProt: P35670-1

ATP7B NM_001406511.1

HGVSc / HGVSpc.2304dupCp.Met769HisfsTer26

Exon rankExon 9 of 22

frameshift

Prot: NP_001393440.1UniProt: P35670-1

ATP7B NM_001406512.1

HGVSc / HGVSpc.2304dupCp.Met769HisfsTer26

Exon rankExon 9 of 22

frameshift

Prot: NP_001393441.1UniProt: P35670-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ATP7B ENST00000242839.10	TSL:1MANE Select	c.2304dupC p.Met769HisfsTer26	frameshift	Exon 8 of 21	Prot: ENSP00000242839.5 UniProt:
	ATP7B ENST00000634844.1	TSL:1	c.2160dupC p.Met721HisfsTer26	frameshift	Exon 8 of 21	Prot: ENSP00000489398.1 UniProt:
	ATP7B ENST00000418097.7	TSL:1	c.2304dupC p.Met769HisfsTer26	frameshift	Exon 8 of 20	Prot: ENSP00000393343.2 UniProt:

ATP7B ENST00000242839.10

TSL:1MANE Select

HGVSc / HGVSpc.2304dupCp.Met769HisfsTer26

Exon rankExon 8 of 21

frameshift

Prot: ENSP00000242839.5UniProt: P35670-1

ATP7B ENST00000634844.1

TSL:1

HGVSc / HGVSpc.2160dupCp.Met721HisfsTer26

Exon rankExon 8 of 21

frameshift

Prot: ENSP00000489398.1UniProt: A0ACI8PQU0

ATP7B ENST00000418097.7

TSL:1

HGVSc / HGVSpc.2304dupCp.Met769HisfsTer26

Exon rankExon 8 of 20

frameshift

Prot: ENSP00000393343.2UniProt: F5H748

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: 0.000118	AC:18	Hom:0	AN:152130	Cov:32
GnomAD2 exomes	AF: 0.000108	AC:27	Hom:	AN:249552	Cov:
GnomAD4 exome	AF: 0.0000958	AC:140	Hom:0	AN:1461892	Cov:31
GnomAD4 genome	AF: 0.000118	AC:18	Hom:0	AN:152130	Cov:32
TOPMed (Bravo)	AF: 0.0000945	AC:25	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000990	AC:3	Hom:0	AN:30296	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000490	AC:6	Hom:0	AN:122696	Cov:
Turkish Variome	AF: 0.000708	AC:4	Hom:0	AN:5176	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00	AC:0	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9622	0.0000959 *	1	10428
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.0000953	4	41958	0.000105	7	66888
SCHEMA(Schizophrenia)	0.000205	25	121906	0.000110	21	190632

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

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
22	-	-	Wilson disease (23)
5	-	-	not provided (5)
1	-	-	ATP7B-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	-2.2

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.020	Details are displayed if max score is > 0.2

Showing 1 of 1 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: rs137853287;

hg19: chr13-52532497;

COSMIC: COSV54435797;

COSMIC: COSV54435797;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar