rs72664233
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001171.6(ABCC6):βc.3775delβ(p.Trp1259GlyfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000046 ( 0 hom., cov: 32)
Exomes π: 0.00016 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 frameshift
NM_001171.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.07
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 16-16157769-CA-C is Pathogenic according to our data. Variant chr16-16157769-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 6563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16157769-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.3775del | p.Trp1259GlyfsTer14 | frameshift_variant | 27/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.3433del | p.Trp1145GlyfsTer14 | frameshift_variant | 27/31 | ||
ABCC6 | NR_147784.1 | n.3437del | non_coding_transcript_exon_variant | 25/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.3775del | p.Trp1259GlyfsTer14 | frameshift_variant | 27/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.3775del | p.Trp1259GlyfsTer14 | frameshift_variant, NMD_transcript_variant | 27/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.*784del | 3_prime_UTR_variant, NMD_transcript_variant | 25/29 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152082Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000839 AC: 21AN: 250336Hom.: 0 AF XY: 0.0000885 AC XY: 12AN XY: 135538
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GnomAD4 exome AF: 0.000159 AC: 233AN: 1461404Hom.: 0 Cov.: 33 AF XY: 0.000182 AC XY: 132AN XY: 727044
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74304
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Pathogenic, no assertion criteria provided | research | PXE International | Mar 01, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2009 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Trp1259Glyfs*14) 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 (rs72664233, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 10835643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6563). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2020 | 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; This variant is associated with the following publications: (PMID: 19904211, 19339160, 10835642, 10835643, 29800625, 15727254, 11536079, 16835894, 16086317) - |
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 | Feb 24, 2022 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at