rs59593133

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001171.6(ABCC6):c.2224A>G(p.Ile742Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,908 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 80 hom., cov: 32)

Exomes 𝑓: 0.016 ( 339 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0170

Publications

8 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003428489).

BP6

Variant 16-16182435-T-C is Benign according to our data. Variant chr16-16182435-T-C is described in ClinVar as Benign. ClinVar VariationId is 433264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.2224A>G	p.Ile742Val	missense_variant	Exon 17 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.2224A>G	p.Ile742Val	missense_variant	Exon 17 of 31	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000456970.6 link	n.2224A>G		non_coding_transcript_exon_variant	Exon 17 of 29	2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 link	n.2224A>G		non_coding_transcript_exon_variant	Exon 17 of 32	5		ENSP00000483331.2	A0A8C8Q0G8

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3767

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0541

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0183

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0369

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.0267

GnomAD2 exomes

AF:

0.0164

AC:

4114

AN:

251476

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.0524

Gnomad AMR exome

AF:

0.00833

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

AF:

0.0162

AC:

23655

AN:

1461674

Hom.:

339

Cov.:

AF XY:

0.0168

AC XY:

12216

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.0568

AC:

1899

AN:

33462

American (AMR)

AF:

0.00892

AC:

399

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

391

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0378

AC:

3261

AN:

86246

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0457

AC:

259

AN:

5668

European-Non Finnish (NFE)

AF:

0.0146

AC:

16208

AN:

1111942

Other (OTH)

AF:

0.0192

AC:

1160

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

1445

2889

4334

5778

7223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.0248

AC:

3773

AN:

152234

Hom.:

Cov.:

AF XY:

0.0239

AC XY:

1778

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0541

AC:

2248

AN:

41538

American (AMR)

AF:

0.0182

AC:

279

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.0367

AC:

177

AN:

4818

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0138

AC:

940

AN:

68004

Other (OTH)

AF:

0.0265

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

181

361

542

722

903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0158

Hom.:

Bravo

AF:

0.0268

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.0517

AC:

227

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.0180

AC:

2189

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0171

EpiControl

AF:

0.0180

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:2

Mar 01, 2021

PXE International

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Arterial calcification, generalized, of infancy, 2

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudoxanthoma elasticum, forme fruste

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.32

CADD

Benign

0.044

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.057

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.1

L;L

PhyloP100

0.017

PrimateAI

Benign

0.33

PROVEAN

Benign

0.26

N;.

REVEL

Benign

0.24

Sift

Benign

0.33

T;.

Sift4G

Benign

0.19

T;T

Polyphen

0.0

B;.

Vest4

0.047

MPC

0.058

ClinPred

0.00061

GERP RS

-0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.079

gMVP

0.32

Mutation Taster

=97/3

polymorphism (auto)

(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