rs72664227

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The ENST00000205557.12(ABCC6):c.1999del(p.Ala667GlnfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ABCC6
ENST00000205557.12 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 0.114

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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-16182874-GC-G is Pathogenic according to our data. Variant chr16-16182874-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16182874-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.1999del	p.Ala667GlnfsTer21	frameshift_variant	16/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.1657del	p.Ala553GlnfsTer21	frameshift_variant	16/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.2036del		non_coding_transcript_exon_variant	16/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.1999del	p.Ala667GlnfsTer21	frameshift_variant	16/31	1	NM_001171.6	ENSP00000205557	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.1999del	p.Ala667GlnfsTer21	frameshift_variant, NMD_transcript_variant	16/32	5		ENSP00000483331
ABCC6	ENST00000456970.6 linkuse as main transcript	c.1999del	p.Ala667GlnfsTer21	frameshift_variant, NMD_transcript_variant	16/29	2		ENSP00000405002		O95255-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249004

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134812

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000359

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 11, 2023	This sequence change creates a premature translational stop signal (p.Ala667Glnfs*21) 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. ClinVar contains an entry for this variant (Variation ID: 433256). This variant is also known as 1995delG. This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 11536079, 16835894, 17617515). This variant is present in population databases (rs72664228, gnomAD 0.003%). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as c.1995delG using alternate nomenclature; This variant is associated with the following publications: (PMID: 16127278, 11536079, 15723264, 22277295, 16835894) -

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

PXE International

Mar 02, 2021

- -

ABCC6-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2023

The ABCC6 c.1999delG variant is predicted to result in a frameshift and premature protein termination (p.Ala667Glnfs*21). In the literature this variant is also referred to as c.1995delG. This variant has been reported in individuals with pseudoxanthoma elasticum (Heterozygous state, Le Saux et al. 2001. PubMed ID: 11536079; Heterozygous state, Schulz et al. 2006. PubMed ID: 16835894; Table S1, Boraldi et al. 2021. PubMed ID: 34205333; Supplemental Table S1, Stumpf et al. 2022. PubMed ID: 35261845) and heritable ectopic mineralization (Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.0036% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16276731-GC-G) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/433256/). This variant is interpreted as 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

Jun 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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