rs193922102

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The ENST00000242839.10(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
ENST00000242839.10 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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2122-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2122-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

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:

AN:

1460566

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726666

show subpopulations

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:

AN:

152328

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74492

show subpopulations

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.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -
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	Baylor Genetics	Mar 03, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 27, 2024	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. -
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. -

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2024

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over