13-51958491-C-T

Variant names:

• chr13-51958491-C-T
• rs61733684
• NM_000053.4:c.2175G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4 BP6_Very_Strong BP7 BS2

The NM_000053.4(ATP7B):​c.2175G>A​(p.Arg725Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,614,198 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (9 hom.)
• Consequence: ATP7B NM_000053.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: -0.523
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.23).
• BP6: Variant 13-51958491-C-T is Benign according to our data. Variant chr13-51958491-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.523 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.2175G>A	p.Arg725Arg	synonymous	Exon 8 of 21	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2175G>A	p.Arg725Arg	synonymous	Exon 9 of 22	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2175G>A	p.Arg725Arg	synonymous	Exon 9 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.2175G>A	p.Arg725Arg	synonymous	Exon 8 of 21	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000418097.7	TSL:1	c.2175G>A	p.Arg725Arg	synonymous	Exon 8 of 20	ENSP00000393343.2	F5H748
	ATP7B	ENST00000448424.7	TSL:1	c.1923G>A	p.Arg641Arg	synonymous	Exon 6 of 19	ENSP00000416738.3	E7ET55

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 483 AN: 152186 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00707

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00457

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00314 AC: 783 AN: 249558 AF XY: 0.00316

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00617

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00363 AC: 5306 AN: 1461894 Hom.: 9 Cov.: 31 AF XY: 0.00353 AC XY: 2569 AN XY: 727248

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26136

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

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86258

European-Finnish (FIN) AF: 0.00563 AC: 301 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00414 AC: 4603 AN: 1112012

Other (OTH) AF: 0.00291 AC: 176 AN: 60396

GnomAD4 genome AF: 0.00318 AC: 484 AN: 152304 Hom.: 4 Cov.: 32 AF XY: 0.00328 AC XY: 244 AN XY: 74482

African (AFR) AF: 0.000866 AC: 36 AN: 41554

American (AMR) AF: 0.00216 AC: 33 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00707 AC: 75 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00459 AC: 312 AN: 68038

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00427 Hom.: 3

Bravo AF: 0.00234

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	7	Wilson disease (7)
-	-	4	not provided (5)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Uncertain	1.0
PhyloP100		-0.52
Mutation Taster		=94/6	polymorphism

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: rs61733684; hg19: chr13-52532627;