NM_000053.4:c.2292C>T

Variant names:

• chr13-51958374-G-A
• rs372979339
• NM_000053.4:c.2292C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000053.4(ATP7B):​c.2292C>T​(p.Phe764Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1 B:3
• Conservation: PhyloP100: 0.108

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=0.108 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.2292C>T	p.Phe764Phe	synonymous_variant	Exon 8 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.2292C>T	p.Phe764Phe	synonymous_variant	Exon 8 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249564 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135400

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Pathogenic:8 Uncertain:1

Apr 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This synonymous variant causes a C>T nucleotide change in exon 8 of the ATP7B protein. This variant has been reported in many individuals affected with Wilson disease (PMID: 15967699, 16207219, 27022412, 31059521, 32613181, 33640437, 33763395, 35271763, 36096368, 36343861). RNA extracted from both compound heterozygous and homozygous individuals affected with Wilson disease showed exon 8 skipping (PMID: 35271763). This result was not replicated in a mini-gene assay, where no exon 8 skipping was observed, possibly suggesting tissue specificity (PMID: 36343861). This variant has been identified in 5/280992 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 764 of the ATP7B mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATP7B protein. This variant is present in population databases (rs372979339, gnomAD 0.004%). This variant has been observed in individual(s) with Wilson disease (PMID: 31059521, 33640437, 33763395; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 157937). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Jan 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

Jun 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.2292C>T; p.Phe764Phe variant (rs372979339, ClinVar Variation ID: 157937) is reported as a polymorphism in individuals with Wilson disease (Dong 2016, Todorov 2005, Vrabelova 2005), but without specifying the genotype. However, recently this variant been seen in several compound heterozygous (confirmed in trans) and homozygous individuals with Wilson disease without any other molecular explanation for disease (Espinos 2020, Fang 2021, Panzer 2022). In a Wilson disease cohort, this variant was found in 14 out of 560 in cases where there was only one reported disease causing variant (Panzer 2022). This variant is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This is a synonymous variant and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant does not alter splicing. However, splicing analysis on cultured fibroblasts demonstrate increased skipping of exon 8 (Panzer 2022) and splicing analysis on leukocytes demonstrate transcription similar to wild type (Xu 2023). Based on available information, this variant is considered to be likely pathogenic. References: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. PMID: 27022412. Espinós C et al. Are the new genetic tools for diagnosis of Wilson disease helpful in clinical practice? JHEP Rep. 2020 Apr 18;2(4):100114. PMID: 32613181. Fang Y et al. Clinical and Genetic Spectra of Inherited Liver Disease in Children in China. Front Pediatr. 2021 Mar 4;9:631620. PMID: 33763395. Panzer M et al. Synonymous mutation in adenosine triphosphatase copper-transporting beta causes enhanced exon skipping in Wilson disease. Hepatol Commun. 2022 Jul;6(7):1611-1619. PMID: 35271763. Todorov T et al. Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet. 2005 Nov;68(5):474-6. PMID: 16207219. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85. PMID: 15967699. Xu WQ et al. Pathogenicity of Intronic and Synonymous Variants of ATP7B in Wilson Disease. J Mol Diagn. 2023 Jan;25(1):57-67. PMID: 36343861. -

Jul 21, 2024

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We found this HOM variant in a 7 yo patient with Wilson disease. -

Sep 21, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATP7B c.2292C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, preliminary reports provided experimental evidence that this might affect mRNA splicing, resulting in partial splice defect, with an in-frame skipping of exon 8 (Wilson_2009, Panzer_2019); in addition, the deletion of exon 8 at the protein level was shown to result in decreased protein level, mislocalization of the shorter protein, and CHO cells expressing ATP7B-delEx8 showed severe inability to tolerate copper (Wilson_2009). The variant allele was found at a frequency of 7.6e-06 in 394326 control chromosomes (gnomAD v2.1 and v3.1 datasets). The variant, c.2292C>T, has been reported earlier in the literature in multiple cohorts of Wilson Disease patients without specifying the genotype (e.g. Todorov_2005, Vrabelova_2005, Dong_2016). However, recently it was also found in several homozygous- and compound heterozygous individuals (with a pathogenic variant in trans), who were affected with Wilson Disease (Singh_2019, Panzer_2019, Collins_2021, Fang_2021). In addition, a recent report based on literature/database reviews, cited the variant in 11 patients affected with Wilson disease, noting that all carried a well-known second variant, and the allele frequency of the variant c.2292C>T was found to be >650-fold higher in this Wilson disease cohort than in public databases (Espinos_2020). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=1), VUS (n=1) or Likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jun 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2019

Molecular Diagnostics, Microbiology, Virology, Parasitology and Genetics, Sofia University, St. Kliment Ohridski

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Phe764Phe variant in ATP7B has been found in 1 Bulgarian and 1 Egyptian families and was segregated with the disease and associated with low ceruloplasmin levels in carriers for this variant. -

not provided Pathogenic:1 Benign:1

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATP7B: PM2:Supporting, BP4, BP7 -

Oct 11, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; This variant is associated with the following publications: (PMID: 16207219, 27022412, 35271763, 36343861, 33763395, 36096368) -

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATP7B-related disorder Benign:1

Oct 06, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.2
DANN	Benign	0.65

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: rs372979339; hg19: chr13-52532510;