rs72657693
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_001171.6(ABCC6):āc.3145T>Gā(p.Ser1049Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 33)
Exomes š: 0.000047 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 missense
NM_001171.6 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 4.49
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 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
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.3145T>G | p.Ser1049Ala | missense_variant | 23/31 | ENST00000205557.12 | NP_001162.5 | |
ABCC6 | NM_001351800.1 | c.2803T>G | p.Ser935Ala | missense_variant | 23/31 | NP_001338729.1 | ||
ABCC6 | NR_147784.1 | n.3007T>G | non_coding_transcript_exon_variant | 22/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.3145T>G | p.Ser1049Ala | missense_variant | 23/31 | 1 | NM_001171.6 | ENSP00000205557 | P1 | |
ABCC6 | ENST00000622290.5 | c.3145T>G | p.Ser1049Ala | missense_variant, NMD_transcript_variant | 23/32 | 5 | ENSP00000483331 | |||
ABCC6 | ENST00000456970.6 | c.*354T>G | 3_prime_UTR_variant, NMD_transcript_variant | 22/29 | 2 | ENSP00000405002 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
3
AN:
152182
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000478 AC: 12AN: 251216Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135900
GnomAD3 exomes
AF:
AC:
12
AN:
251216
Hom.:
AF XY:
AC XY:
6
AN XY:
135900
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461408Hom.: 0 Cov.: 33 AF XY: 0.0000578 AC XY: 42AN XY: 726994
GnomAD4 exome
AF:
AC:
69
AN:
1461408
Hom.:
Cov.:
33
AF XY:
AC XY:
42
AN XY:
726994
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
GnomAD4 genome
AF:
AC:
3
AN:
152182
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74342
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
2
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Uncertain:1
Uncertain significance, no assertion criteria provided | research | PXE International | Feb 16, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2023 | This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1049 of the ABCC6 protein (p.Ser1049Ala). This variant is present in population databases (rs72657693, gnomAD 0.01%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 16835894). ClinVar contains an entry for this variant (Variation ID: 433302). 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. - |
Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 11, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Pathogenic
Sift
Benign
T;.
Sift4G
Benign
T;.
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at