rs72664209

Positions:

chr16-16173283-C-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PP3_StrongPP5_Very_Strong

The NM_001171.6(ABCC6):c.2787+1G>T variant causes a splice donor 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

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]

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 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.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-16173283-C-A is Pathogenic according to our data. Variant chr16-16173283-C-A is described in ClinVar as [Likely_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	Effect	MANE
ABCC6	NM_001171.6 linkuse as main transcript	c.2787+1G>T	splice_donor_variant	ENST00000205557.12
ABCC6	NM_001351800.1 linkuse as main transcript	c.2445+1G>T	splice_donor_variant
ABCC6	NR_147784.1 linkuse as main transcript	n.2649+1G>T	splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.2787+1G>T	splice_donor_variant		1	NM_001171.6	P1	O95255-1
ABCC6	ENST00000576683.1 linkuse as main transcript	n.275G>T	non_coding_transcript_exon_variant	3/3	3
ABCC6	ENST00000456970.6 linkuse as main transcript	c.2612+1G>T	splice_donor_variant, NMD_transcript_variant		2			O95255-3
ABCC6	ENST00000622290.5 linkuse as main transcript	c.2787+1G>T	splice_donor_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

151994

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.000124

AC:

AN:

250980

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135778

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 SAS 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.:

Cov.:

AF XY:

0.000326

AC XY:

237

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000432

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000164

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000247

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2023	Observed in patients with pseudoxanthoma elasticum in published literature (Le Saux et al., 2000; Plomp et al., 2008; Pfendner et al., 2008); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; functional studies show variant leads to a new splice site and aberrant splicing, which causes a frameshift and results in an abnormal and truncated protein (Nitschke et al., 2012); This variant is associated with the following publications: (PMID: 16835894, 16086317, 11427982, 24008425, 25525159, 10835643, 21167005, 20189652, 22209248, 29800625, 30215852, 28102862, 15723264, 18253096, 17617515, 33352936, 34205333, 32489700, 10835642, 31589614, 33820832, 35261845, 34925949, 34906475) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ABCC6: PM3:Very Strong, PVS1, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 11, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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. -

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 13, 2012	- -
Pathogenic, no assertion criteria provided	research	PXE International	-	- -

Arterial calcification, generalized, of infancy, 2

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2023	- -

ABCC6-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2023

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 (http://gnomad.broadinstitute.org/variant/16-16267140-C-A). Variants that disrupt the consensus splice donor site in ABCC6 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

GERP RS

4.5

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over