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

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 splice_donor, intron

Scores

2
4
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 3.69
Variant links:
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 was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 16-16173283-C-A is Pathogenic according to our data. Variant chr16-16173283-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16173283-C-A is described in Lovd as [Pathogenic]. Variant chr16-16173283-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCC6NM_001171.6 linkc.2787+1G>T splice_donor_variant, intron_variant Intron 21 of 30 ENST00000205557.12 NP_001162.5
ABCC6NM_001351800.1 linkc.2445+1G>T splice_donor_variant, intron_variant Intron 21 of 30 NP_001338729.1
ABCC6NR_147784.1 linkn.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
ABCC6ENST00000205557.12 linkc.2787+1G>T splice_donor_variant, intron_variant Intron 21 of 30 1 NM_001171.6 ENSP00000205557.7 O95255-1
ABCC6ENST00000576683.1 linkn.275G>T non_coding_transcript_exon_variant Exon 3 of 3 3
ABCC6ENST00000456970.6 linkn.2612+1G>T splice_donor_variant, intron_variant Intron 20 of 28 2 ENSP00000405002.2 O95255-3
ABCC6ENST00000622290.5 linkn.2787+1G>T splice_donor_variant, intron_variant Intron 21 of 31 5 ENSP00000483331.2 A0A8C8Q0G8

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
151994
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.0000657
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000124
AC:
31
AN:
250980
AF XY:
0.000118
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000256
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000333
AC:
486
AN:
1461636
Hom.:
0
Cov.:
35
AF XY:
0.000326
AC XY:
237
AN XY:
727086
show subpopulations
African (AFR)
AF:
0.0000598
AC:
2
AN:
33470
American (AMR)
AF:
0.0000224
AC:
1
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86246
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53390
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5616
European-Non Finnish (NFE)
AF:
0.000432
AC:
480
AN:
1111990
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60370
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
25
50
74
99
124
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
151994
Hom.:
0
Cov.:
31
AF XY:
0.000108
AC XY:
8
AN XY:
74222
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41370
American (AMR)
AF:
0.0000657
AC:
1
AN:
15230
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10592
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000309
AC:
21
AN:
67998
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000249
Hom.:
0
Bravo
AF:
0.000166
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ABCC6: PM3:Very Strong, PVS1, PM2 -

Jan 11, 2024
Revvity Omics, Revvity
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jun 03, 2025
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
-
PXE International
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research

- -

Jan 13, 2012
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Arterial calcification, generalized, of infancy, 2 Pathogenic:2
Jan 13, 2012
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Jun 30, 2023
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ABCC6-related disorder Pathogenic:1
Aug 01, 2024
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

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
Nov 04, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
0.82
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.94
D
GERP RS
4.5
Mutation Taster
=7/93
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.75
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.98
Position offset: 2
DS_DL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72664209; hg19: chr16-16267140; API