13-51974632-G-T

Variant names:

• chr13-51974632-G-T
• rs756718353
• NM_000053.4:c.588C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_000053.4(ATP7B):​c.588C>A​(p.Asp196Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:3
• Conservation: PhyloP100: 0.0170
• Publications: 10 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: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• PP5: Variant 13-51974632-G-T is Pathogenic according to our data. Variant chr13-51974632-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554931.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15255475). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.588C>A	p.Asp196Glu	missense_variant	Exon 2 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.588C>A	p.Asp196Glu	missense_variant	Exon 2 of 21	1	NM_000053.4	ENSP00000242839.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248962 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460310 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 726264

African (AFR) AF: 0.00 AC: 0 AN: 33336

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60312

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000413 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Pathogenic:5 Uncertain:3

Mar 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 196 of the ATP7B protein (p.Asp196Glu). This variant is present in population databases (rs756718353, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease (PMID: 24119323, 26483271, 30702195). ClinVar contains an entry for this variant (Variation ID: 554931). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3_Strong+PP4 -

May 21, 2021

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glutamic acid at codon 196 of the ATP7B protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown that this variant did not have a significant impact on cell viability when exposed to a range of copper concentrations, however, the clinical significance of this study is unknown (Macintyre, et al., poster #65, ASHG 2009). This variant has been observed in over a dozen individuals affected with autosomal recessive Wilson disease, with at least 6 confirmed to have a pathogenic variant, indicating that this variant contributes to disease (PMID: 17876883, 24119323, 26483271, 27022412, 30702195, 30884209, 34470610, 36872857, 37701133). This variant has been identified in 4/248962 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Nov 09, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Dec 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.588C>A; p.Asp196Glu variant (rs756718353) is reported in the literature in several individuals affected with Wilson disease (Ye 2007, Dong 2016, Li 2019, Ni 2013). However, a second pathogenic variant was only reported in a minority of cases (Li 2019, Poon 2016, Ni 2013). This variant was found in two individuals with two additional pathogenic variants where the phase of the variants is unknown and this variant was found in an individual with a homozygous pathogenic variant (Li 2019, Poon 2016, Qian 2019). This variant is also reported in ClinVar (Variation ID: 554931). This variant is only observed on four alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.497). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. 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. Li X et al. Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants. Hum Mutat. 2019 May;40(5):552-565. PMID: 30702195. Ni W et al. Zinc monotherapy and a low-copper diet are beneficial in patients with Wilson disease after liver transplantation. CNS Neurosci Ther. 2013 Nov;19(11):905-7. PMID: 24119323. Poon KS et al. Targeted next-generation sequencing of the ATP7B gene for molecular diagnosis of Wilson disease. Clin Biochem. 2016 Jan;49(1-2):166-71. PMID: 26483271. Qian Z et al. Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. Mol Genet Genomic Med. 2019 May;7(5):e649. PMID: 30884209. Ye S et al. Wilson disease: identification of two novel mutations and clinical correlation in Eastern Chinese patients. World J Gastroenterol. 2007 Oct 14;13(38):5147-50. PMID: 17876883. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;T;.;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.72	T;T;T;T;T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	-0.13	N;.;N;N;.;.;.
PhyloP100		0.017
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.52	N;N;N;N;N;.;N
REVEL	Uncertain	0.50
Sift	Benign	1.0	T;T;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;P;B;B
Vest4		0.16
MutPred		0.79		Gain of disorder (P = 0.1828);Gain of disorder (P = 0.1828);Gain of disorder (P = 0.1828);Gain of disorder (P = 0.1828);Gain of disorder (P = 0.1828);Gain of disorder (P = 0.1828);Gain of disorder (P = 0.1828);
MVP		0.86
MPC		0.059
ClinPred		0.062	T
GERP RS		2.1
PromoterAI		-0.026	Neutral
Varity_R		0.040
gMVP		0.45
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs756718353; hg19: chr13-52548768;