rs66492417
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_001171.6(ABCC6):c.2304C>A(p.Tyr768Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,430 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
ABCC6
NM_001171.6 stop_gained
NM_001171.6 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.57
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 Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 16-16178909-G-T is Pathogenic according to our data. Variant chr16-16178909-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 433270.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16178909-G-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC6 | NM_001171.6 | c.2304C>A | p.Tyr768Ter | stop_gained | 18/31 | ENST00000205557.12 | |
ABCC6 | NM_001351800.1 | c.1962C>A | p.Tyr654Ter | stop_gained | 18/31 | ||
ABCC6 | NR_147784.1 | n.2341C>A | non_coding_transcript_exon_variant | 18/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.2304C>A | p.Tyr768Ter | stop_gained | 18/31 | 1 | NM_001171.6 | P1 | |
ABCC6 | ENST00000622290.5 | c.2304C>A | p.Tyr768Ter | stop_gained, NMD_transcript_variant | 18/32 | 5 | |||
ABCC6 | ENST00000456970.6 | c.2304C>A | p.Tyr768Ter | stop_gained, NMD_transcript_variant | 18/29 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461430Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6AN XY: 727018
GnomAD4 exome
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9
AN:
1461430
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36
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6
AN XY:
727018
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:1
Pathogenic, no assertion criteria provided | research | PXE International | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2023 | ClinVar contains an entry for this variant (Variation ID: 433270). This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 11536079, 34906475). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr768*) in the ABCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
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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