rs368465318
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_001171.6(ABCC6):c.2943G>T(p.Gln981His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,611,422 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 missense
NM_001171.6 missense
Scores
6
11
2
Clinical Significance
Conservation
PhyloP100: 1.24
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a domain ABC transmembrane type-1 2 (size 281) in uniprot entity MRP6_HUMAN there are 30 pathogenic changes around while only 5 benign (86%) in NM_001171.6
PP3
MetaRNN computational evidence supports a deleterious effect, 0.844
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.2943G>T | p.Gln981His | missense_variant | 22/31 | ENST00000205557.12 | NP_001162.5 | |
ABCC6 | NM_001351800.1 | c.2601G>T | p.Gln867His | missense_variant | 22/31 | NP_001338729.1 | ||
ABCC6 | NR_147784.1 | n.2805G>T | non_coding_transcript_exon_variant | 21/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.2943G>T | p.Gln981His | missense_variant | 22/31 | 1 | NM_001171.6 | ENSP00000205557.7 | ||
ABCC6 | ENST00000456970.6 | n.*152G>T | non_coding_transcript_exon_variant | 21/29 | 2 | ENSP00000405002.2 | ||||
ABCC6 | ENST00000622290.5 | n.2943G>T | non_coding_transcript_exon_variant | 22/32 | 5 | ENSP00000483331.2 | ||||
ABCC6 | ENST00000456970 | n.*152G>T | 3_prime_UTR_variant | 20/28 | 2 | ENSP00000405002.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000572 AC: 14AN: 244840Hom.: 0 AF XY: 0.0000599 AC XY: 8AN XY: 133496
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459186Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 725878
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74376
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1
Uncertain significance, criteria provided, single submitter | research | PXE International | Feb 16, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2022 | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 981 of the ABCC6 protein (p.Gln981His). This variant is present in population databases (rs368465318, gnomAD 0.07%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 18157818). ClinVar contains an entry for this variant (Variation ID: 433434). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC6 protein function. 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
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of disorder (P = 0.1535);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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