NM_000053.4:c.2544C>T

Variant names:

• chr13-51950303-G-A
• rs200996053
• NM_000053.4:c.2544C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000053.4(ATP7B):​c.2544C>T​(p.Gly848Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000631 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G848G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (1 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 0.389
• Publications: 3 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 13-51950303-G-A is Benign according to our data. Variant chr13-51950303-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 312387.

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.2544C>T	p.Gly848Gly	synonymous	Exon 10 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2544C>T	p.Gly848Gly	synonymous	Exon 11 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2544C>T	p.Gly848Gly	synonymous	Exon 11 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.2544C>T	p.Gly848Gly	synonymous	Exon 10 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2400C>T	p.Gly800Gly	synonymous	Exon 10 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.2544C>T	p.Gly848Gly	synonymous	Exon 10 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000597 AC: 149 AN: 249530 AF XY: 0.000613

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.000830

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000649 AC: 949 AN: 1461882 Hom.: 1 Cov.: 35 AF XY: 0.000650 AC XY: 473 AN XY: 727244

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

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

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86258

European-Finnish (FIN) AF: 0.000861 AC: 46 AN: 53412

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

European-Non Finnish (NFE) AF: 0.000718 AC: 798 AN: 1112008

Other (OTH) AF: 0.000563 AC: 34 AN: 60396

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74444

African (AFR) AF: 0.0000481 AC: 2 AN: 41540

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68010

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

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.000355

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	4	Wilson disease (7)
-	5	-	not provided (5)
-	1	-	ATP7B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.68
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 2

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

Other links and lift over

dbSNP: rs200996053; hg19: chr13-52524439;