rs72664209
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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):c.2787+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000317 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00033 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 splice_donor, intron
NM_001171.6 splice_donor, intron
Scores
2
4
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.69
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
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 16-16173283-C-A is Pathogenic according to our data. Variant chr16-16173283-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16173283-C-A is described in Lovd as [Pathogenic]. Variant chr16-16173283-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.2787+1G>T | splice_donor_variant, intron_variant | ENST00000205557.12 | NP_001162.5 | |||
ABCC6 | NM_001351800.1 | c.2445+1G>T | splice_donor_variant, intron_variant | NP_001338729.1 | ||||
ABCC6 | NR_147784.1 | n.2649+1G>T | splice_donor_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.2787+1G>T | splice_donor_variant, intron_variant | 1 | NM_001171.6 | ENSP00000205557.7 | ||||
ABCC6 | ENST00000576683.1 | n.275G>T | non_coding_transcript_exon_variant | 3/3 | 3 | |||||
ABCC6 | ENST00000456970.6 | n.2612+1G>T | splice_donor_variant, intron_variant | 2 | ENSP00000405002.2 | |||||
ABCC6 | ENST00000622290.5 | n.2787+1G>T | splice_donor_variant, intron_variant | 5 | ENSP00000483331.2 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 151994Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000124 AC: 31AN: 250980Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135778
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GnomAD4 exome AF: 0.000333 AC: 486AN: 1461636Hom.: 0 Cov.: 35 AF XY: 0.000326 AC XY: 237AN XY: 727086
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GnomAD4 genome AF: 0.000164 AC: 25AN: 151994Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74222
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2024 | Observed in patients with pseudoxanthoma elasticum in published literature (PMID: 10835642, 18253096, 17617515); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35583931, 36368308, 16835894, 16086317, 11427982, 24008425, 25525159, 10835643, 21167005, 20189652, 22209248, 29800625, 30215852, 28102862, 18253096, 17617515, 33352936, 34205333, 32489700, 31589614, 33820832, 35261845, 34925949, 34906475, 10835642, 15723264) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change affects a donor splice site in intron 21 of the ABCC6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). This variant is present in population databases (rs72664209, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with pseudoxanthoma elasticum or generalized arterial calcification of infancy (PMID: 10835642, 16835894, 18253096, 22209248, 24008425, 25265166). This variant is also known as IVS21+1G>T. ClinVar contains an entry for this variant (Variation ID: 6560). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | ABCC6: PM3:Very Strong, PVS1, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2024 | - - |
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 13, 2012 | - - |
Pathogenic, no assertion criteria provided | research | PXE International | - | - - |
Arterial calcification, generalized, of infancy, 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 13, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 30, 2023 | - - |
ABCC6-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 01, 2024 | The ABCC6 c.2787+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in patients with pseudoxanthoma elasticum (reported as IVS21+1G>T in Le Saux et al. 2000. PubMed ID: 10835642; Nitschke et al. 2012. PubMed ID: 22209248; reported in compound heterozygous state in Li et al. 2014. PubMed ID: 24008425; Kranenburg et al. 2018. PubMed ID: 29800625). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in ABCC6 are expected to be pathogenic. 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 | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at