rs72664227
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001171.6(ABCC6):c.1999del(p.Ala667GlnfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 frameshift
NM_001171.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.114
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 16-16182874-GC-G is Pathogenic according to our data. Variant chr16-16182874-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16182874-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.1999del | p.Ala667GlnfsTer21 | frameshift_variant | 16/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.1657del | p.Ala553GlnfsTer21 | frameshift_variant | 16/31 | ||
ABCC6 | NR_147784.1 | n.2036del | non_coding_transcript_exon_variant | 16/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.1999del | p.Ala667GlnfsTer21 | frameshift_variant | 16/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.1999del | p.Ala667GlnfsTer21 | frameshift_variant, NMD_transcript_variant | 16/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.1999del | p.Ala667GlnfsTer21 | frameshift_variant, NMD_transcript_variant | 16/29 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249004Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134812
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GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461886Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 14AN XY: 727242
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 11, 2023 | This sequence change creates a premature translational stop signal (p.Ala667Glnfs*21) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433256). This variant is also known as 1995delG. This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 11536079, 16835894, 17617515). This variant is present in population databases (rs72664228, gnomAD 0.003%). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 26, 2021 | Frameshift 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; Also known as c.1995delG using alternate nomenclature; This variant is associated with the following publications: (PMID: 16127278, 11536079, 15723264, 22277295, 16835894) - |
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | PXE International | Mar 02, 2021 | - - |
ABCC6-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 09, 2023 | The ABCC6 c.1999delG variant is predicted to result in a frameshift and premature protein termination (p.Ala667Glnfs*21). In the literature this variant is also referred to as c.1995delG. This variant has been reported in individuals with pseudoxanthoma elasticum (Heterozygous state, Le Saux et al. 2001. PubMed ID: 11536079; Heterozygous state, Schulz et al. 2006. PubMed ID: 16835894; Table S1, Boraldi et al. 2021. PubMed ID: 34205333; Supplemental Table S1, Stumpf et al. 2022. PubMed ID: 35261845) and heritable ectopic mineralization (Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.0036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16276731-GC-G) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/433256/). This variant is interpreted as pathogenic. - |
Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at