rs193922102

chr13-51958552-A-Cchr13-51958552-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000053.4(ATP7B):c.2122-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATP7B NM_000053.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005096
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.476

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-51958552-A-C is Pathogenic according to our data. Variant chr13-51958552-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2122-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2122-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460566 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726666

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74492

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This variant causes a T to G nucleotide substitution at the -8 position of intron 7 of the ATP7B gene. This variant has been reported in individuals affected with Wilson disease (PMID: 12325021, 18728530, 20967755, 31172689, 34400371). In two of these affected individuals, this variant has been determined to be homozygous (PMID: 12325021) or compound heterozygous (PMID: 31172689) with another pathogenic variant in the same gene, indicating that this variant contributes to Wilson disease in an autosomal recessive manner. RT-PCR analysis of lymphocytes from an individual homozygous for this variant showed the predominant transcript had an in-frame deletion of exon 8 (PMID: 12325021). In the same study, RNA extracted from lymphocytes from a healthy control also produced a transcript with an in-frame deletion of exon 8, in addition to the full length transcript. These results have been replicated with a minigene assay (Wilson 2009, thesis, University of Alberta). To our knowledge, protein functional consequence of exon 8 deletion has not been investigated in the literature. However, exon 8 encodes transmembrane domains of the ATP7B protein, where many pathogenic missense variants have been reported. In summary, this variant has been shown to increase the proportion of an aberrant transcript with in-frame deletion of exon 8 that encodes a functionally important transmembrane domains and have been observed in individuals with Wilson disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The c.2122-8T>G variant in ATP7B has been previously reported in three individuals with Wilson disease, including one homozygous individual and one individual who had a second uncertain ATP7B variant (Loudianos 2002, Nicastro 2010, Zappu 2008). This variant was absent from large population studies. An RT-PCR study performed on leukocytes from an individual homozygous for the variant indicated skipping of exon 8 (Loudianos 2002). While there is at least 1 transcript in GTEX that does not include exon 8, there are multiple pathogenic variants in this exon which suggests that this region may be important for protein function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM2, PM4, PP4, PS3_Supporting, PM3_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change falls in intron 7 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Wilson disease (PMID: 12325021, 20967755, 31172689). ClinVar contains an entry for this variant (Variation ID: 35705). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 12325021). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2022	Functional studies by RT-PCR analysis demonstrated the c.2122-8 T>G variant results in the prevalent production of a transcript with the in-frame deletion of exon 8 (Loudianos et al., 2002); Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 18728530, 11076401, 12325021, 34400371, 20967755) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 12, 2020	PVS1_strong, PS4_moderate, PM2, PM3 -

ATP7B-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2023

The ATP7B c.2122-8T>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with Wilson disease (Loudianos et al 2002. PubMed ID: 12325021; Nicastro E et al 2010. PubMed ID: 20967755; Li X et al 2019. PubMed ID: 31172689; Couchonnal E et al 2021. PubMed ID: 34400371). Functional studies using RT-PCR analysis showed that this variant may either result in a in frame deletion of exon 8 or activate a cryptic splice site that leads to a frameshift and truncated protein (Loudianos et al 2002. PubMed ID: 12325021). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	15
Dann	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0051
dbscSNV1_RF	Benign	0.68
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 15
DS_AL_spliceai		0.50		Position offset: -8

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922102; hg19: chr13-52532688;