rs63750459

Variant names:

Variant summary

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

The NM_001171.6(ABCC6):c.3389C>T(p.Thr1130Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,613,736 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.84

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 16 pathogenic changes around while only 0 benign (100%) in NM_001171.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

PP5

Variant 16-16163110-G-A is Pathogenic according to our data. Variant chr16-16163110-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16163110-G-A is described in Lovd as [Pathogenic]. Variant chr16-16163110-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCC6	NM_001171.6 link	c.3389C>T	p.Thr1130Met	missense_variant	Exon 24 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 link	c.3047C>T	p.Thr1016Met	missense_variant	Exon 24 of 31		NP_001338729.1
ABCC6	NR_147784.1 link	n.3169-1546C>T		intron_variant	Intron 22 of 28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.3389C>T	p.Thr1130Met	missense_variant	Exon 24 of 31	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000622290.5 link	n.3389C>T		non_coding_transcript_exon_variant	Exon 24 of 32	5		ENSP00000483331.2	A0A8C8Q0G8
ABCC6	ENST00000456970.6 link	n.*516-1546C>T		intron_variant	Intron 22 of 28	2		ENSP00000405002.2	O95255-3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251178

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000992

AC:

145

AN:

1461506

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

727038

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:

0.00

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000276

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:2

Mar 01, 2021

PXE International

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Abnormality of the eye

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Undetermined rare ocular disorder with frequency of less than eight patients -

not provided

Pathogenic:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1130 of the ABCC6 protein (p.Thr1130Met). This variant is present in population databases (rs63750459, gnomAD 0.009%). This missense change has been observed in individual(s) with autosomal recessive pseudoxanthoma elasticum (PXE) (PMID: 12673275, 14631379, 15086542, 18347285, 32873932). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6569). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCC6 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive inherited pseudoxanthoma elasticum;C1867450:Pseudoxanthoma elasticum, forme fruste;C3276161:Arterial calcification, generalized, of infancy, 2

Pathogenic:1

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.5

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.44

MVP

0.97

MPC

0.39

ClinPred

0.94

GERP RS

5.3

Varity_R

0.73

gMVP

0.76

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