rs63750608
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_001171.6(ABCC6):āc.4025T>Cā(p.Ile1342Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 31)
Exomes š: 0.000029 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 missense
NM_001171.6 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 7.50
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 7 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001171.6
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
?
Variant 16-16154889-A-G is Pathogenic according to our data. Variant chr16-16154889-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 433345.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr16-16154889-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.4025T>C | p.Ile1342Thr | missense_variant | 28/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.3683T>C | p.Ile1228Thr | missense_variant | 28/31 | ||
ABCC6 | NR_147784.1 | n.3687T>C | non_coding_transcript_exon_variant | 26/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.4025T>C | p.Ile1342Thr | missense_variant | 28/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000576204.6 | n.888T>C | non_coding_transcript_exon_variant | 1/2 | 5 | ||||
ABCC6 | ENST00000456970.6 | c.*1034T>C | 3_prime_UTR_variant, NMD_transcript_variant | 26/29 | 2 | ||||
ABCC6 | ENST00000622290.5 | c.*197T>C | 3_prime_UTR_variant, NMD_transcript_variant | 29/32 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152008Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000815 AC: 2AN: 245280Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 132956
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1460436Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 726416
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152008Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74246
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | PXE International | Feb 17, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 06, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1342 of the ABCC6 protein (p.Ile1342Thr). This variant is present in population databases (rs63750608, gnomAD 0.002%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 17617515, 26029710). ClinVar contains an entry for this variant (Variation ID: 433345). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;.
Vest4
MutPred
Loss of stability (P = 0.006);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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