rs72653744

Positions:

chr16-16163009-G-A

Variant summary

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

The NM_001171.6(ABCC6):c.3490C>T(p.Arg1164Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,614,070 control chromosomes in the GnomAD database, including 1 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

ABCC6
NM_001171.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.06

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 16-16163009-G-A is Pathogenic according to our data. Variant chr16-16163009-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16163009-G-A 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.3490C>T	p.Arg1164Ter	stop_gained	24/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.3148C>T	p.Arg1050Ter	stop_gained	24/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.3169-1445C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.3490C>T	p.Arg1164Ter	stop_gained	24/31	1	NM_001171.6	ENSP00000205557	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.3490C>T	p.Arg1164Ter	stop_gained, NMD_transcript_variant	24/32	5		ENSP00000483331
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*516-1445C>T		intron_variant, NMD_transcript_variant		2		ENSP00000405002		O95255-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251284

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000233

AC:

340

AN:

1461778

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

178

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000260

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000112

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000205

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2015	The p.Arg1164X variant in ABCC6 has been previously reported in the homozygous s tate in one family with Pseudoxanthoma Elasticum (PXE; Struk 2000) and in 2 hete rozygous individuals with PXE in which another variant was not identified (Melon i 2001, Chassaing 2004). This variant has also been identified in 0.05% (4/8652 ) East Asian chromosomes by the Exome Aggregation Consortium (http://exac.broadi nstitute.org/; dbSNP rs72653744). Although this variant has been seen in the gen eral population, its frequency is low enough to be consistent with a recessive c arrier frequency. This nonsense variant leads to a premature termination codon a t position 1164, which is predicted to lead to a truncated or absent protein. Co mplete loss of ABCC6 function is an established disease mechanism for PXE. In su mmary, this variant meets our criteria to be classified as pathogenic for PXE in an autosomal recessive manner (www.partners.org/personalizedmedicine/lmm). -
Pathogenic, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	Reported in the heterozygous state in three patients with pseudoxanthoma elasticum from two families, although a second ABCC6 variant was not identified in these cases (Meloni et al., 2001; Chassaing et al., 2004); 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; This variant is associated with the following publications: (PMID: 1179012, 25525159, 28696355, 34205333, 34906475, 33879512, 31980526, 17617515, 11179012, 30056620, 29948180, 31269855, 30879837, 15086542, 28186352, 11439001, 10954200, 29480367, 31589614, 31345219) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg1164*) 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 (rs72653744, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with pseudoxanthoma elasticum (PMID: 11179012, 11439001). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6572). 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. -

ABCC6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2024

The ABCC6 c.3490C>T variant is predicted to result in premature protein termination (p.Arg1164*). This variant has been reported to be causative for autosomal recessive pseudoxanthoma elasticum (PXE; Struk et al. 2000. PubMed ID: 10954200; Meloni et al. 2001. PubMed ID: 11439001; Boraldi et al. 2021. PubMed ID: 34205333; Table S1, Saeidian et al. 2022. PubMed ID: 34906475). This variant has also been reported in an individual with acute aortic dissection (Table 1, Zheng et al. 2018. PubMed ID: 30056620). This variant is reported in 0.065% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in ABCC6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 03, 2021

ACMG classification criteria: PVS1, PS4, PM2, 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

Jun 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.41

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.40

MutationTaster

Benign

1.0

Vest4

0.91

GERP RS

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.45

Position offset: -16

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