rs72653705
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001171.6(ABCC6):c.3088C>T(p.Arg1030Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000316 in 1,613,370 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000031 ( 1 hom. )
Consequence
ABCC6
NM_001171.6 stop_gained
NM_001171.6 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 5.96
Genes affected
ABCC6 (HGNC:57): (ATP binding cassette subfamily C member 6) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). The encoded protein, a member of the MRP subfamily, is involved in multi-drug resistance. Mutations in this gene cause pseudoxanthoma elasticum. Alternatively spliced transcript variants that encode different proteins have been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 16-16165841-G-A is Pathogenic according to our data. Variant chr16-16165841-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16165841-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.3088C>T | p.Arg1030Ter | stop_gained | 23/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.2746C>T | p.Arg916Ter | stop_gained | 23/31 | ||
ABCC6 | NR_147784.1 | n.2950C>T | non_coding_transcript_exon_variant | 22/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.3088C>T | p.Arg1030Ter | stop_gained | 23/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.3088C>T | p.Arg1030Ter | stop_gained, NMD_transcript_variant | 23/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.*297C>T | 3_prime_UTR_variant, NMD_transcript_variant | 22/29 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152186Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250842Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135808
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461066Hom.: 1 Cov.: 33 AF XY: 0.0000316 AC XY: 23AN XY: 726818
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Arg1030*) in the ABCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). This variant is present in population databases (rs72653705, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of pseudoxanthoma elasticum (PMID: 11536079, 15459974). ClinVar contains an entry for this variant (Variation ID: 433300). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 27, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 08, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11536079, 25525159, 31589614, 18513494, 15459974) - |
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | PXE International | Mar 12, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -14
Find out detailed SpliceAI scores and Pangolin per-transcript scores at