16-16155007-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PP3_StrongPP5_Moderate

The NM_001171.6(ABCC6):c.3907G>C(p.Ala1303Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,562,484 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 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.89

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

arterial calcification, generalized, of infancy, 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
autosomal recessive inherited pseudoxanthoma elasticum
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P
arterial calcification of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ABCC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001171.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 16-16155007-C-G is Pathogenic according to our data. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-16155007-C-G is described in CliVar as Pathogenic. Clinvar id is 433335.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.3907G>C	p.Ala1303Pro	missense_variant	Exon 28 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 link	c.3907G>C	p.Ala1303Pro	missense_variant	Exon 28 of 31	1	NM_001171.6	ENSP00000205557.7		O95255-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000600

AC:

AN:

166638

AF XY:

0.0000112

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1410368

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

696958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32136

American (AMR)

AF:

0.00

AC:

AN:

37266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25272

East Asian (EAS)

AF:

0.00

AC:

AN:

36682

South Asian (SAS)

AF:

0.00

AC:

AN:

80182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0000249

AC:

AN:

1086102

Other (OTH)

AF:

0.00

AC:

AN:

58494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000203

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:1

Mar 01, 2021

PXE International

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Pathogenic:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1303 of the ABCC6 protein (p.Ala1303Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with pseudoxanthoma elasticum (PMID: 12673275, 16086317, 18157818). 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: 433335). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;.

PhyloP100

7.9

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.3

D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.93

Loss of catalytic residue at A1303 (P = 0.0047);.;

MVP

0.94

MPC

0.46

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.96

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over