rs148211042
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_005689.4(ABCB6):c.2168G>A(p.Arg723Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,613,838 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R723W) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0011 ( 2 hom. )
Consequence
ABCB6
NM_005689.4 missense
NM_005689.4 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 6.02
Genes affected
ABCB6 (HGNC:47): (ATP binding cassette subfamily B member 6 (LAN blood group)) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. ABC proteins transport various molecules across extra- and intra-cellular membranes. This protein is a member of the heavy metal importer subfamily and plays a role in porphyrin transport. This gene is the molecular basis of the Langereis (Lan) blood group antigen and mutations in this gene underlie familial pseudohyperkalemia and dyschromatosis universalis hereditaria. [provided by RefSeq, Mar 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000736 (112/152232) while in subpopulation NFE AF= 0.00134 (91/68022). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 112 AD,BG gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCB6 | NM_005689.4 | c.2168G>A | p.Arg723Gln | missense_variant | 16/19 | ENST00000265316.9 | |
ABCB6 | NM_001349828.2 | c.2030G>A | p.Arg677Gln | missense_variant | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCB6 | ENST00000265316.9 | c.2168G>A | p.Arg723Gln | missense_variant | 16/19 | 1 | NM_005689.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000736 AC: 112AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000766 AC: 191AN: 249416Hom.: 1 AF XY: 0.000859 AC XY: 116AN XY: 135102
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GnomAD4 exome AF: 0.00113 AC: 1646AN: 1461606Hom.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 826AN XY: 727084
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial pseudohyperkalemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 218181). This missense change has been observed in individual(s) with familial pseudohyperkalemia (PMID: 24947683, 27151991). This variant is present in population databases (rs148211042, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 723 of the ABCB6 protein (p.Arg723Gln). Experimental studies have shown that this missense change affects ABCB6 function (PMID: 27151991). 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
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
T
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