rs732774

Variant names:

• chr13-51949672-C-T
• rs732774
• NM_000053.4:c.2855G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-51949672-C-T
• chr13-51949672-C-A
• chr13-51949672-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.2855G>A​(p.Arg952Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,613,064 control chromosomes in the GnomAD database, including 270,218 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.56 (24237 hom., cov: 33)
  • Exomes 𝑓: 0.58 (245981 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:18
• Conservation: PhyloP100: 2.25
• Publications: 93 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: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=3.4731627E-4).
• BP6: Variant 13-51949672-C-T is Benign according to our data. Variant chr13-51949672-C-T is described in ClinVar as Benign. ClinVar VariationId is 35708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

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.2855G>A	p.Arg952Lys	missense	Exon 12 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2855G>A	p.Arg952Lys	missense	Exon 13 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2855G>A	p.Arg952Lys	missense	Exon 13 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.2855G>A	p.Arg952Lys	missense	Exon 12 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2711G>A	p.Arg904Lys	missense	Exon 12 of 21	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.2855G>A	p.Arg952Lys	missense	Exon 12 of 20	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85554 AN: 151968 Hom.: 24228 Cov.: 33

Gnomad AFR AF: 0.527

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.601

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.585

GnomAD2 exomes AF: 0.567 AC: 141220 AN: 249058 AF XY: 0.566

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.582

Gnomad OTH exome AF: 0.583

GnomAD4 exome AF: 0.578 AC: 844929 AN: 1460978 Hom.: 245981 Cov.: 60 AF XY: 0.577 AC XY: 419281 AN XY: 726858

African (AFR) AF: 0.530 AC: 17725 AN: 33466

American (AMR) AF: 0.633 AC: 28329 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 14987 AN: 26126

East Asian (EAS) AF: 0.402 AC: 15938 AN: 39690

South Asian (SAS) AF: 0.521 AC: 44969 AN: 86244

European-Finnish (FIN) AF: 0.605 AC: 32121 AN: 53094

Middle Eastern (MID) AF: 0.633 AC: 3649 AN: 5768

European-Non Finnish (NFE) AF: 0.587 AC: 652489 AN: 1111506

Other (OTH) AF: 0.575 AC: 34722 AN: 60364

GnomAD4 genome AF: 0.563 AC: 85608 AN: 152086 Hom.: 24237 Cov.: 33 AF XY: 0.563 AC XY: 41830 AN XY: 74342

African (AFR) AF: 0.527 AC: 21850 AN: 41458

American (AMR) AF: 0.597 AC: 9124 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1972 AN: 3470

East Asian (EAS) AF: 0.408 AC: 2107 AN: 5168

South Asian (SAS) AF: 0.523 AC: 2518 AN: 4814

European-Finnish (FIN) AF: 0.601 AC: 6366 AN: 10586

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39853 AN: 67982

Other (OTH) AF: 0.587 AC: 1239 AN: 2112

Alfa AF: 0.575 Hom.: 89144

Bravo AF: 0.563

TwinsUK AF: 0.587 AC: 2177

ALSPAC AF: 0.591 AC: 2276

ESP6500AA AF: 0.521 AC: 1965

ESP6500EA AF: 0.595 AC: 4896

ExAC AF: 0.562 AC: 67900

Asia WGS AF: 0.527 AC: 1827 AN: 3478

EpiCase AF: 0.591

EpiControl AF: 0.591

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	Wilson disease (9)
-	-	7	not specified (7)
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Benign	0.77
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.016	T
MetaRNN	Benign	0.00035	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.41	N
PhyloP100		2.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.2	N
REVEL	Uncertain	0.43
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.043
MPC		0.060
ClinPred		0.0077	T
GERP RS		6.1
Varity_R		0.12
gMVP		0.59
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs732774; hg19: chr13-52523808; COSMIC: COSV54436520; COSMIC: COSV54436520;