rs63750457

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_001171.6(ABCC6):c.3491G>A(p.Arg1164Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.08

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 11 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 70) in uniprot entity MRP6_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_001171.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.786

PP5

Variant 16-16163008-C-T is Pathogenic according to our data. Variant chr16-16163008-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16163008-C-T is described in Lovd as [Pathogenic]. Variant chr16-16163008-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCC6	NM_001171.6 linkuse as main transcript	c.3491G>A	p.Arg1164Gln	missense_variant	24/31	ENST00000205557.12
ABCC6	NM_001351800.1 linkuse as main transcript	c.3149G>A	p.Arg1050Gln	missense_variant	24/31
ABCC6	NR_147784.1 linkuse as main transcript	n.3169-1444G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.3491G>A	p.Arg1164Gln	missense_variant	24/31	1	NM_001171.6	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.3491G>A	p.Arg1164Gln	missense_variant, NMD_transcript_variant	24/32	5
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*516-1444G>A		intron_variant, NMD_transcript_variant		2			O95255-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152168

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251256

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000938

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

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:

0.0000942

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, no assertion criteria provided	research	PXE International	Mar 01, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1164 of the ABCC6 protein (p.Arg1164Gln). This variant is present in population databases (rs63750457, gnomAD 0.01%). This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 16086317, 16410789, 17617515, 18157818, 27133371, 28186352). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.4021G>A. ClinVar contains an entry for this variant (Variation ID: 372295). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ABCC6 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2016	The R1164Q variant in the ABCC6 gene has been previously reported in both the homozygous and compound heterozygous state with another ABCC6 variant (Miksch et al., 2005; Vanakker et al., 2008; Dibi et al., 2016). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R1164Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. ACMG criteria therefor result in classifying this variant as likely pathogenic; and the unlikely possibility that it is benign cannot be excluded. -

ABCC6-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2023

The ABCC6 c.3491G>A variant is predicted to result in the amino acid substitution p.Arg1164Gln. This variant has been reported in individuals with autosomal recessive pseudoxanthoma elasticum (PXE; Table 1, Miksch et al. 2005. PubMed ID: 16086317; Figure 1, Ringpfeil et al. 2006. PubMed ID: 16410789; Dibi et al. 2016. Clin Med Rev Case Rep 3:129; Table 3, Iwanaga et al. 2017. PubMed ID: 28186352; Boraldi et al. 2021. PubMed ID: 34205333; Table S1, Saeidian et al. 2021. PubMed ID: 34906475; Table S1, Stumpf et al. 2022. PubMed ID: 35261845). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16256865-C-T). 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

Sep 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0078

BayesDel_noAF

Uncertain

-0.020

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.48

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.62

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.57

Sift

Benign

0.23

Sift4G

Benign

0.30

Polyphen

0.57

Vest4

0.73

MutPred

0.79

Loss of methylation at R1164 (P = 0.0243);

MVP

0.82

MPC

0.082

ClinPred

0.45

GERP RS

3.4

Varity_R

0.12

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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