chr16-16173283-C-A
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001171.6(ABCC6):c.2787+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000317 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001171.6 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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ABCC6 | NM_001171.6 | c.2787+1G>T | splice_donor_variant, intron_variant | Intron 21 of 30 | ENST00000205557.12 | NP_001162.5 | ||
ABCC6 | NM_001351800.1 | c.2445+1G>T | splice_donor_variant, intron_variant | Intron 21 of 30 | NP_001338729.1 | |||
ABCC6 | NR_147784.1 | n.2649+1G>T | splice_donor_variant, intron_variant | Intron 20 of 28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC6 | ENST00000205557.12 | c.2787+1G>T | splice_donor_variant, intron_variant | Intron 21 of 30 | 1 | NM_001171.6 | ENSP00000205557.7 | |||
ABCC6 | ENST00000576683.1 | n.275G>T | non_coding_transcript_exon_variant | Exon 3 of 3 | 3 | |||||
ABCC6 | ENST00000456970.6 | n.2612+1G>T | splice_donor_variant, intron_variant | Intron 20 of 28 | 2 | ENSP00000405002.2 | ||||
ABCC6 | ENST00000622290.5 | n.2787+1G>T | splice_donor_variant, intron_variant | Intron 21 of 31 | 5 | ENSP00000483331.2 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 151994Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.000124 AC: 31AN: 250980 AF XY: 0.000118 show subpopulations
GnomAD4 exome AF: 0.000333 AC: 486AN: 1461636Hom.: 0 Cov.: 35 AF XY: 0.000326 AC XY: 237AN XY: 727086 show subpopulations
GnomAD4 genome AF: 0.000164 AC: 25AN: 151994Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8AN XY: 74222 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:8
This sequence change affects a donor splice site in intron 21 of the ABCC6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCC6 are known to be pathogenic (PMID: 11536079, 17617515). This variant is present in population databases (rs72664209, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with pseudoxanthoma elasticum or generalized arterial calcification of infancy (PMID: 10835642, 16835894, 18253096, 22209248, 24008425, 25265166). This variant is also known as IVS21+1G>T. ClinVar contains an entry for this variant (Variation ID: 6560). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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ABCC6: PM3:Very Strong, PVS1, PM2 -
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Observed in patients with pseudoxanthoma elasticum in published literature (PMID: 10835642, 18253096, 17617515); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 35583931, 36368308, 16835894, 16086317, 11427982, 24008425, 25525159, 10835643, 21167005, 20189652, 22209248, 29800625, 30215852, 28102862, 18253096, 17617515, 33352936, 34205333, 32489700, 31589614, 33820832, 35261845, 34925949, 34906475, 10835642, 38927735, 37558402, 15723264) -
Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:2
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Arterial calcification, generalized, of infancy, 2 Pathogenic:2
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ABCC6-related disorder Pathogenic:1
The ABCC6 c.2787+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in patients with pseudoxanthoma elasticum (reported as IVS21+1G>T in Le Saux et al. 2000. PubMed ID: 10835642; Nitschke et al. 2012. PubMed ID: 22209248; reported in compound heterozygous state in Li et al. 2014. PubMed ID: 24008425; Kranenburg et al. 2018. PubMed ID: 29800625). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in ABCC6 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pseudoxanthoma elasticum Pathogenic:1
Variant summary: ABCC6 c.2787+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ABCC6 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Two predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 250980 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC6 causing Pseudoxanthoma Elasticum, allowing no conclusion about variant significance. c.2787+1G>T has been reported in the literature in multiple compound heterozygous or homozygous individuals affected with Pseudoxanthoma Elasticum (e.g. Le Saux_2000, Plomp_2008, Kuzaj_2014, Saeidian_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25265166, 10835642, 18253096, 34906475). ClinVar contains an entry for this variant (Variation ID: 6560). Based on the evidence outlined above, the variant was classified as pathogenic. -
Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at