rs72653772

Positions:

chr16-16190246-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_001171.6(ABCC6):c.1553G>A(p.Arg518Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,614,070 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R518R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.57

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 14 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 61) in uniprot entity MRP6_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_001171.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 16-16190246-C-T is Pathogenic according to our data. Variant chr16-16190246-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16190246-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ABCC6	NM_001171.6 linkuse as main transcript	c.1553G>A	p.Arg518Gln	missense_variant	12/31	ENST00000205557.12
ABCC6	NM_001351800.1 linkuse as main transcript	c.1211G>A	p.Arg404Gln	missense_variant	12/31
ABCC6	NR_147784.1 linkuse as main transcript	n.1590G>A		non_coding_transcript_exon_variant	12/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.1553G>A	p.Arg518Gln	missense_variant	12/31	1	NM_001171.6	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.1553G>A	p.Arg518Gln	missense_variant, NMD_transcript_variant	12/32	5
ABCC6	ENST00000456970.6 linkuse as main transcript	c.1553G>A	p.Arg518Gln	missense_variant, NMD_transcript_variant	12/29	2			O95255-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251288

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135838

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:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000923

AC:

135

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000926

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000105

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000210

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

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	Oct 03, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the ABCC6 protein (p.Arg518Gln). This variant is present in population databases (rs72653772, gnomAD 0.01%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 15459974, 20075945). ClinVar contains an entry for this variant (Variation ID: 265018). 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 expected to disrupt ABCC6 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34906475, 27057999, 30879837, 12384774, 15086542, 25264593, 25595835, 28102862, 31589614, 34205333, 35261845, 36317459, 32873932, 38112957, 15459974, 37259549, 20075945, 23485117) -

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:1

Pathogenic, no assertion criteria provided

research

PXE International

Mar 01, 2021

- -

ABCC6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2024

The ABCC6 c.1553G>A variant is predicted to result in the amino acid substitution p.Arg518Gln. This variant has been reported as a founder variant in individuals of North African descent with autosomal recessive pseudoxanthoma elasticum (Legrand et al. 2017. PubMed ID: 28102862; Chassaing et al. 2004. PubMed ID: 15086542; Le Saux et al 2002. PubMed ID: 12384774; Ramsay et al. 2009. PubMed ID: 19339160). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

H;H

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.99

MVP

0.93

MPC

0.44

ClinPred

0.93

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.89

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