rs72653706

Positions:

• chr16-16163078-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001171.6(ABCC6):​c.3421C>T​(p.Arg1141Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,922 control chromosomes in the GnomAD database, including 5 homozygotes. 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: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: ABCC6 NM_001171.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30
• Conservation: PhyloP100: 3.00

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]

ACMG classification

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 16-16163078-G-A is Pathogenic according to our data. Variant chr16-16163078-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16163078-G-A is described in Lovd as [Pathogenic]. Variant chr16-16163078-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC6	NM_001171.6	c.3421C>T	p.Arg1141Ter	stop_gained	24/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1	c.3079C>T	p.Arg1027Ter	stop_gained	24/31		NP_001338729.1
ABCC6	NR_147784.1	n.3169-1514C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12	c.3421C>T	p.Arg1141Ter	stop_gained	24/31	1	NM_001171.6	ENSP00000205557	P1
ABCC6	ENST00000622290.5	c.3421C>T	p.Arg1141Ter	stop_gained, NMD_transcript_variant	24/32	5		ENSP00000483331
ABCC6	ENST00000456970.6	c.*516-1514C>T		intron_variant, NMD_transcript_variant		2		ENSP00000405002

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00141 AC: 355 AN: 251296 Hom.: 0 AF XY: 0.00154 AC XY: 209 AN XY: 135858

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00166 AC: 2431 AN: 1461600 Hom.: 5 Cov.: 33 AF XY: 0.00171 AC XY: 1245 AN XY: 727076

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00282

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.00107 AC XY: 80 AN XY: 74490

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00195 Hom.: 1

Bravo AF: 0.00108

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00139 AC: 169

EpiCase AF: 0.00191

EpiControl AF: 0.00190

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:13

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 06, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABCC6: PM3:Very Strong, PVS1, PP1:Strong, PM2:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Arg1141*) 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). This variant is present in population databases (rs72653706, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 10835642, 12714611, 17617515, 22209248, 26982014). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6559). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2016	- -
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	GeneDx	Mar 28, 2022	Nonsense 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; Expression studies of the R1141X variant in leukocytes and cultured fibroblasts from affected individuals homozygous for R1141X demonstrate mRNA instability and absence of the protein in immunohistochemistry studies (Hu et al., 2003); Early speculation that heterozygosity for R1141X may increase the risk of coronary artery disease has not been confirmed in a large cohort study (Trip et al., 2002; Hornstrup et al., 2011).; This variant is associated with the following publications: (PMID: 29800625, 29709427, 31646622, 32646269, 22209248, 12176944, 19929409, 10835643, 25525159, 24352041, 12714611, 23746223, 27133371, 10811882, 23675997, 16086317, 21831958, 26982014, 16854481, 16384891, 16133423, 14631379, 24008425, 28102862, 18800149, 12384774, 30206659, 29722917, 30985656, 31980526, 34440381, 33812167, 34426522, 31589614, 33726816) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 12, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive inherited pseudoxanthoma elasticum Pathogenic:9

Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Aug 04, 2023	This variant is predicted to cause a premature termination of the protein and the resultant protein will probably lack part of the ABC transmembrane type-1 domain and the entire ABC transporter 2 domain of the protein [UniProt]; this will likely result in loss-of-function. Due to the introduction of a premature stop codon, this aberrant transcript will likely be targeted by the nonsense-mediated mRNA decay (NMD) mechanism [PMID: 15040442]. The identified variant was previously reported in individuals with pseudoxanthoma elasticum and observed to segregate with disease in related individuals [PMID: 10835642, 12714611, 17617515, 22209248, 26982014]. Loss-of-function variants in ABCC6 are known to be pathogenic [PMID: 11536079, 17617515]. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 25, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	research	PXE International	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with generalized infantile arterial calcification 2 (MIM#614473), pseudoxanthoma elasticum (MIM#264800) and forme fruste pseudoxanthoma elasticum (MIM#177850). (I) 0106 - This gene is associated with autosomal recessive disease. OIder publications suggest dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability with age-dependent severity has been well reported (PMID: 28102862). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (396 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many of these variants have been reported times as pathogenic, and are reported in many individuals with pseudoxanthoma elasticum or generalized arterial calcification (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, in both homozygous or compound heterozygous individuals with pseudoxanthoma elasticum or generalized arterial calcification of infancy. It represents one of the most common variants within Caucasian populations (ClinVar, PMID: 28102862). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 04, 2024	Criteria applied: PVS1,PM3_STR,PP4; Identified as compund heterozygous with NM_001171.6:c.3413G>A -

Arterial calcification, generalized, of infancy, 2 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. This variant was detected in homozygous state. -

ABCC6-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 09, 2024	The ABCC6 c.3421C>T variant is predicted to result in premature protein termination (p.Arg1141*). This variant has been reported to be causative for autosomal recessive pseudoxanthoma elasticum (PXE) (Ringpfeil et al. 2000. PubMed ID: 10811882, ABCC6 gene was reported as MRP6 gene; Hu et al. 2003. PubMed ID: 12714611; Miksch et al. 2005. PubMed ID: 16086317). In addition, several studies have reported a significantly increased risk of coronary artery disease in carriers of the ABCC6 p.Arg1141* variant (Trip et al. 2002. PubMed ID: 12176944; Köblös et al. 2010. PubMed ID: 19929409). Nonsense variants in ABCC6 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 30, 2022	PVS1, PS3, PM3_Strong -

Cutis laxa;C0332563:Papule Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 24, 2014

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 05, 2021

ACMG classification criteria: PVS1, PS3, PM3 -

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	0.30	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A
Vest4		0.89
GERP RS		4.4

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

Other links and lift over

dbSNP: rs72653706; hg19: chr16-16256935;