NM_000053.4:c.19_20delCA

Variant names:

• chr13-52011317-CTG-C
• rs749363958
• NM_000053.4:c.19_20delCA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000053.4(ATP7B):​c.19_20delCA​(p.Gln7AspfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ATP7B NM_000053.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:9
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 188 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.19_20delCA	p.Gln7AspfsTer14	frameshift_variant	Exon 1 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.19_20delCA	p.Gln7AspfsTer14	frameshift_variant	Exon 1 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152262 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 38 AN: 249432 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1461862 Hom.: 0 AF XY: 0.000124 AC XY: 90 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152380 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74512

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000170

EpiCase AF: 0.000218

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Pathogenic:4 Uncertain:5

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln7Aspfs*14) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs749363958, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 15967699). ClinVar contains an entry for this variant (Variation ID: 419611). For these reasons, this variant has been classified as Pathogenic. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PM3+PP4 -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 01, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift c.19_20del(p.Gln7AspfsTer14) variant in ATP7B gene has been reported previously to be correlating with Wilson disease (Vrabelova et al. 2005), and has also been reported in both homozygous and compound heterozygous state in individuals asymptomatic for Wilson disease (Loudianos et al. 2016; Stalke et al. 2019). The p.Gln7AspfsTer14 variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic / Uncertain Siginificance. This variant causes a frameshift starting with codon Glutamine 7, changes this amino acid to Aspartic Acid residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Gln7AspfsTer14. Loss of function variants have been previously reported to be disease causing. However, experimental evidence suggests that this variant's mRNA and protein is expressed in amounts comparable to the wild-type and the copper export capacity is also comparable to the wild-type, indicating that this variant is able to bypass non-sense mediated decay by translation reinitiation (Stalke et al. 2019). For these reasons, this variant is classified as a Variant of Uncertain Significance (VUS). -

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 1 of the ATP7B gene, creating a frameshift and premature translation stop signal. While this variant is expected to result in nonsense-mediated mRNA decay, clinical findings and functional study results indicate that the effect of this variant appears to be mitigated, presumably by an alternate translation initiation. This variant has been reported as homozygous in a 5-year-old girl who exhibited no symptoms of Wilson disease, no abnormalities in liver biopsy, and ATP7B mRNA expression levels in the liver comparable to healthy controls (PMID: 30723317). When a minigene construct carrying this variant was overexpressed in HEK293T cells, it resulted in ATP7B mRNA and protein expression comparable to wild-type in size and amount, as well as normal copper export capacity (PMID: 30723317). This variant has also been reported in an asymptomatic adult in compound heterozygous state with a known pathogenic variant in the same gene (PMID: 26752957). These observations indicate that the predicted loss of ATP7B function due to this variant can be bypassed, presumably by alternate translation initiation using a downstream methionine. This variant has been reported in additional individuals affected with Wilson disease with unspecified second mutation (PMID: 15967699, 34620762). This variant has been identified in 39/280828 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 30, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:2

Dec 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 20, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported homozygous in a female pediatric patient with no symptoms of Wilson disease or abnormalities on liver biopsy (PMID: 30723317); Expression of mRNA in liver cells of a patient homozygous for the variant was in the range of healthy controls and in-vitro expression assays found mRNA and protein levels comparable to wild type, suggesting that the variant may bypass nonsense-mediated mRNA decay (NMD) allowing normal copper export (PMID: 30723317); This variant is associated with the following publications: (PMID: 18371106, 29649982, 31169307, 23486543, 30291343, 31980526, 26752957, 15967699, 30723317, 36437915, 34620762, 30476936) -

not specified Uncertain:1

Jan 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP7B c.19_20delCA (p.Gln7AspfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. However, in vitro functional studies (Stalke_2019) found the variant mRNA and protein are expressed in size and amount comparable to wild-type while copper export capacity was also comparable to wild-type; these results indicate that c.19_20del in ATP7B is able to bypass NMD by translation reinitiation. The variant allele was found at a frequency of 0.00015 in 249432 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. c.19_20delCA has been reported in the literature in individuals affected with Wilson Disease, however with limited information (i.e. second allele not reported/specified) in one case (Vrabelova_2005) and in two individuals diagnosed with the hepatic form of Wilson Disease who were compound heterozygous together with a pathogenic variant (p.H1069Q), but who had ATP7B peptide levels (assayed from dried blood spots) that were mostly within or near the normal range (Collins_2021). In addition, multiple compound heterozygous or homozygous individuals were found to be asymptomatic for ATP7B-related conditions (Loudianos_2016, Stalke_2019, Nicastro_2021), were found to be asymptomatic for ATP7B-related conditions. Thus, these reports do not provide unequivocal conclusions about association of the variant with Wilson Disease. The following publications have been ascertained in the context of this evaluation (PMID: 18371106, 15967699, 26752957, 23486543, 29649982, 30723317, 33640437, 37205945). ClinVar contains an entry for this variant (Variation ID: 419611). Based on the evidence outlined above, the variant was classified as uncertain significance. -

ATP7B-related disorder Uncertain:1

Nov 12, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.19_20delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln7Aspfs*14). This variant has been reported in an individual with Wilson disease (Vrabelova et al. 2005. PubMed ID: 15967699). Of note, this variant was also detected in the compound heterozygous state in an asymptomatic adult patient (Loudianos et al. 2016. PubMed ID: 26752957) and in the homozygous state in an asymptomatic adolescent patient (Stalke et al. 2019. PubMed ID: 30723317). Additional function studies showed that this variant bypasses nonsense-mediated mRNA decay and protein function is similar to wild-type (Stalke et al. 2019. PubMed ID: 30723317). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52585453-CTG-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs749363958; hg19: chr13-52585453;