16-16178961-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_001171.6(ABCC6):c.2252T>A(p.Met751Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,326 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.40

Publications

4 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: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001171.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

PP5

Variant 16-16178961-A-T is Pathogenic according to our data. Variant chr16-16178961-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 433266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.2252T>A	p.Met751Lys	missense_variant	Exon 18 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.2252T>A	p.Met751Lys	missense_variant	Exon 18 of 31	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000456970.6 link	n.2252T>A		non_coding_transcript_exon_variant	Exon 18 of 29	2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 link	n.2252T>A		non_coding_transcript_exon_variant	Exon 18 of 32	5		ENSP00000483331.2	A0A8C8Q0G8

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152186

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460140

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726382

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5030

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111948

Other (OTH)

AF:

0.00

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000329

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000283

Hom.:

Bravo

AF:

0.0000453

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

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

- -

Optic atrophy

Pathogenic:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCC6-related disorder

Pathogenic:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCC6 c.2252T>A variant is predicted to result in the amino acid substitution p.Met751Lys. This variant in the heterozygous state was reported in five unrelated patients with pseudoxanthoma elasticum; in a study by the same group, this variant was found in several affected individuals who also carried another protein-truncating variant in this same gene (Hendig et al. 2005. PubMed ID: 15723264; Schulz et al. 2006. PubMed ID: 16835894). However, no additional information was given to conclusively determine pathogenicity (e.g. segregation analysis). Other groups have also reported this variant in multiple individuals with ectopic mineralization disorders (Vanakker et al. 2008. PubMed ID: 18157818; Verschuere et al. 2020. PubMed ID: 32873932; Saeidian et al. 2021. PubMed ID: 34906475). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 751 of the ABCC6 protein (p.Met751Lys). This variant is present in population databases (rs72653786, gnomAD 0.01%). This missense change has been observed in individuals with pseudoxanthoma elasticum (PMID: 16835894, 18157818, 33820832, 34906475, 35261845). ClinVar contains an entry for this variant (Variation ID: 433266). 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 not expected to disrupt ABCC6 protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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

Pathogenic:1

Apr 26, 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

0.17

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.71

D;.

Eigen

Benign

0.074

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

-0.32

N;N

PhyloP100

7.4

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.8

D;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.029

D;T

Polyphen

0.98

D;.

Vest4

0.79

MutPred

0.82

Gain of ubiquitination at M751 (P = 0.0082);Gain of ubiquitination at M751 (P = 0.0082);

MVP

0.82

MPC

0.17

ClinPred

0.90

GERP RS

3.9

Varity_R

0.84

gMVP

0.68

Mutation Taster

=15/85

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