13-51949710-C-G

Position:

• chr13-51949710-C-G

Variant summary

Our verdict is Pathogenic. Variant got 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000242839.10(ATP7B):​c.2817G>C​(p.Trp939Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP7B ENST00000242839.10 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Pathogenic. Variant got 24 ACMG points.

• PS1: Transcript ENST00000242839.10 (ATP7B) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 371483
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000242839.10
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 13-51949710-C-G is Pathogenic according to our data. Variant chr13-51949710-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1409871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.2817G>C	p.Trp939Cys	missense_variant	12/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.2817G>C	p.Trp939Cys	missense_variant	12/21	1	NM_000053.4	ENSP00000242839	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 08, 2021	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with Wilson disease (PMID: 23430908). It has also been observed to segregate with disease in related individuals. This sequence change replaces tryptophan with cysteine at codon 939 of the ATP7B protein (p.Trp939Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces tryptophan with cysteine at codon 939 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it alters a conserved tryptophan residue in the transmembrane domain M5 of the ATP7B protein (a.a. 918 - 946), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). The p.Trp939Cys variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 17272994, 23430908, 30655162), including at least one individual in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 17272994) and in multiple individuals in the homozygous state (PMID: 23430908). A different DNA substitution with the same protein consequence (c.2817G>T p.Trp939Cys) has also been identified in patients with autosomal recessive Wilson disease (ClinVar variation ID: 371483). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.97	D;D;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-12	D;D;D;D;.;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;B;D;D;D
Vest4		0.97
MutPred		0.79		Loss of helix (P = 0.1706);.;.;.;.;Loss of helix (P = 0.1706);
MVP		0.99
MPC		0.46
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: 6

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-52523846;