13-51950424-C-T

Variant names:

• chr13-51950424-C-T
• rs9526811
• NM_000053.4:c.2448-25G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.2448-25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,612,734 control chromosomes in the GnomAD database, including 163,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.36 (11416 hom., cov: 32)
  • Exomes 𝑓: 0.45 (151906 hom.)
• Consequence: ATP7B NM_000053.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.478
• Publications: 8 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-51950424-C-T is Benign according to our data. Variant chr13-51950424-C-T is described in ClinVar as Benign. ClinVar VariationId is 254764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.471 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.2448-25G>A		intron	N/A	NP_000044.2	P35670-1
	ATP7B	NM_001406511.1		c.2448-25G>A		intron	N/A	NP_001393440.1	P35670-1
	ATP7B	NM_001406512.1		c.2448-25G>A		intron	N/A	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.2448-25G>A		intron	N/A	ENSP00000242839.5	P35670-1
	ATP7B	ENST00000634844.1	TSL:1	c.2304-25G>A		intron	N/A	ENSP00000489398.1	B7ZLR4
	ATP7B	ENST00000418097.7	TSL:1	c.2448-25G>A		intron	N/A	ENSP00000393343.2	F5H748

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54354 AN: 152052 Hom.: 11419 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.417

GnomAD2 exomes AF: 0.405 AC: 100851 AN: 249082 AF XY: 0.409

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.407

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.434

GnomAD4 exome AF: 0.450 AC: 657117 AN: 1460564 Hom.: 151906 Cov.: 56 AF XY: 0.448 AC XY: 325423 AN XY: 726644

African (AFR) AF: 0.109 AC: 3649 AN: 33464

American (AMR) AF: 0.369 AC: 16484 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 10559 AN: 26130

East Asian (EAS) AF: 0.355 AC: 14100 AN: 39698

South Asian (SAS) AF: 0.334 AC: 28817 AN: 86206

European-Finnish (FIN) AF: 0.476 AC: 25241 AN: 53048

Middle Eastern (MID) AF: 0.429 AC: 2240 AN: 5216

European-Non Finnish (NFE) AF: 0.477 AC: 529930 AN: 1111772

Other (OTH) AF: 0.433 AC: 26097 AN: 60314

GnomAD4 genome AF: 0.357 AC: 54349 AN: 152170 Hom.: 11416 Cov.: 32 AF XY: 0.358 AC XY: 26659 AN XY: 74388

African (AFR) AF: 0.121 AC: 5043 AN: 41542

American (AMR) AF: 0.378 AC: 5774 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1392 AN: 3468

East Asian (EAS) AF: 0.354 AC: 1834 AN: 5174

South Asian (SAS) AF: 0.339 AC: 1636 AN: 4824

European-Finnish (FIN) AF: 0.474 AC: 5013 AN: 10578

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32300 AN: 67980

Other (OTH) AF: 0.416 AC: 878 AN: 2112

Alfa AF: 0.425 Hom.: 2956

Bravo AF: 0.343

Asia WGS AF: 0.361 AC: 1251 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Wilson disease (4)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.63
PhyloP100		0.48
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs9526811; hg19: chr13-52524560; COSMIC: COSV54440237; COSMIC: COSV54440237;