13-51974966-C-G

Variant names:

• chr13-51974966-C-G
• rs786204643
• NM_000053.4:c.254G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_000053.4(ATP7B):​c.254G>C​(p.Gly85Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G85D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 4.81
• 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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51974966-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3065530.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 13-51974966-C-G is Pathogenic according to our data. Variant chr13-51974966-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2422358.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.254G>C	p.Gly85Ala	missense	Exon 2 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.254G>C	p.Gly85Ala	missense	Exon 3 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.254G>C	p.Gly85Ala	missense	Exon 3 of 22	NP_001393441.1	P35670-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.254G>C	p.Gly85Ala	missense	Exon 2 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.254G>C	p.Gly85Ala	missense	Exon 2 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.254G>C	p.Gly85Ala	missense	Exon 2 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Wilson disease (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.92		Loss of sheet (P = 0.1398)
MVP		0.98
MPC		0.39
ClinPred		1.0	D
GERP RS		5.4
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.82
Mutation Taster		=4/96	disease causing

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: rs786204643; hg19: chr13-52549102;