rs72657702
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePP3_StrongPP5_Moderate
The NM_001171.6(ABCC6):c.37-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000112 in 1,612,818 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 0.000013 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 splice_acceptor
NM_001171.6 splice_acceptor
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.13
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.02016844 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 1, new splice context is: cctctttgtgttccctcaAGtct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 16-16221832-C-T is Pathogenic according to our data. Variant chr16-16221832-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 433372.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16221832-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.37-1G>A | splice_acceptor_variant | ENST00000205557.12 | |||
ABCC6 | NM_001079528.4 | c.37-1G>A | splice_acceptor_variant | ||||
ABCC6 | NM_001351800.1 | c.-337-1G>A | splice_acceptor_variant | ||||
ABCC6 | NR_147784.1 | n.74-1G>A | splice_acceptor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.37-1G>A | splice_acceptor_variant | 1 | NM_001171.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000166 AC: 4AN: 241476Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131864
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460684Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 726668
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74318
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 24, 2022 | This variant was identified together with NM_001171.6:c.3736-1G>A._x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP - |
Likely pathogenic, no assertion criteria provided | research | PXE International | Mar 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at