rs66864704
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_001171.6(ABCC6):āc.1703T>Cā(p.Phe568Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,002 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00034 ( 1 hom., cov: 32)
Exomes š: 0.000047 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 missense
NM_001171.6 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 8.95
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 domain ABC transmembrane type-1 1 (size 282) in uniprot entity MRP6_HUMAN there are 54 pathogenic changes around while only 20 benign (73%) in NM_001171.6
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.959
PP5
?
Variant 16-16188907-A-G is Pathogenic according to our data. Variant chr16-16188907-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 433241.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=2}. Variant chr16-16188907-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.1703T>C | p.Phe568Ser | missense_variant | 13/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.1361T>C | p.Phe454Ser | missense_variant | 13/31 | ||
ABCC6 | NR_147784.1 | n.1740T>C | non_coding_transcript_exon_variant | 13/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.1703T>C | p.Phe568Ser | missense_variant | 13/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.1703T>C | p.Phe568Ser | missense_variant, NMD_transcript_variant | 13/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.1703T>C | p.Phe568Ser | missense_variant, NMD_transcript_variant | 13/29 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000342 AC: 52AN: 152190Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000119 AC: 30AN: 251206Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135844
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461812Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34AN XY: 727192
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GnomAD4 genome ? AF: 0.000342 AC: 52AN: 152190Hom.: 1 Cov.: 32 AF XY: 0.000498 AC XY: 37AN XY: 74350
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2Uncertain:1
Uncertain significance, no assertion criteria provided | research | PXE International | Feb 16, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jan 24, 2023 | The missense c.1703T>C (p.Phe568Ser) variant in ABCC6 gene has been reported previously in multiple individuals affected with pseudoxanthoma elasticum (Ringpfeil et al. 2006; Legrand et al. 2017; Verschuere et al. 2021). The p.Phe568Ser variant is reported with an allele frequency of 0.001% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic. The amino acid change p.Phe568Ser in ABCC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Phe at position 568 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 12, 2023 | ACMG classification criteria: PM3 strong, PP3 supporting, PP4 - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 568 of the ABCC6 protein (p.Phe568Ser). This variant is present in population databases (rs66864704, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of pseudoxanthoma elasticum (PMID: 16410789; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 433241). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC6 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 12, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);
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