rs72657698

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.793A>G(p.Arg265Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0666 in 151,816 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 358 hom., cov: 30)

Exomes 𝑓: 0.037 ( 3822 hom. )

Failed GnomAD Quality Control

Consequence

ABCC6
NM_001171.6 missense, splice_region

Scores

Splicing: ADA: 0.008483

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.0140

Publications

14 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:

ENSG00000305554 (HGNC:):

ENSG00000305554 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=0.0022835135).

BP6

Variant 16-16208729-T-C is Benign according to our data. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.793A>G	p.Arg265Gly	missense_variant, splice_region_variant	Exon 7 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.793A>G	p.Arg265Gly	missense_variant, splice_region_variant	Exon 7 of 31	1	NM_001171.6	ENSP00000205557.7		O95255-1

Frequencies

GnomAD3 genomes

AF:

0.0666

AC:

10110

AN:

151698

Hom.:

359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0599

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.0601

Gnomad ASJ

AF:

0.0709

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.0264

Gnomad FIN

AF:

0.0448

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0802

Gnomad OTH

AF:

0.0685

GnomAD2 exomes

AF:

0.0427

AC:

10355

AN:

242738

AF XY:

0.0431

show subpopulations

Gnomad AFR exome

AF:

0.0482

Gnomad AMR exome

AF:

0.0249

Gnomad ASJ exome

AF:

0.0312

Gnomad EAS exome

AF:

0.0231

Gnomad FIN exome

AF:

0.0378

Gnomad NFE exome

AF:

0.0603

Gnomad OTH exome

AF:

0.0465

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0366

AC:

49797

AN:

1360146

Hom.:

3822

Cov.:

AF XY:

0.0372

AC XY:

25224

AN XY:

678628

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0333

AC:

1060

AN:

31870

American (AMR)

AF:

0.0269

AC:

1175

AN:

43648

Ashkenazi Jewish (ASJ)

AF:

0.0501

AC:

1242

AN:

24788

East Asian (EAS)

AF:

0.0427

AC:

1682

AN:

39386

South Asian (SAS)

AF:

0.0199

AC:

1688

AN:

84616

European-Finnish (FIN)

AF:

0.0479

AC:

2542

AN:

53016

Middle Eastern (MID)

AF:

0.0410

AC:

224

AN:

5458

European-Non Finnish (NFE)

AF:

0.0371

AC:

37847

AN:

1020230

Other (OTH)

AF:

0.0409

AC:

2337

AN:

57134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.344

Heterozygous variant carriers

1983

3965

5948

7930

9913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.0666

AC:

10108

AN:

151816

Hom.:

358

Cov.:

AF XY:

0.0644

AC XY:

4777

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.0598

AC:

2474

AN:

41398

American (AMR)

AF:

0.0600

AC:

913

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.0709

AC:

246

AN:

3470

East Asian (EAS)

AF:

0.0330

AC:

170

AN:

5148

South Asian (SAS)

AF:

0.0262

AC:

126

AN:

4808

European-Finnish (FIN)

AF:

0.0448

AC:

474

AN:

10588

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0802

AC:

5442

AN:

67868

Other (OTH)

AF:

0.0678

AC:

143

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

423

846

1270

1693

2116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0724

Hom.:

217

Bravo

AF:

0.0681

ExAC

AF:

0.0600

AC:

7282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Department of Ophthalmology and Visual Sciences Kyoto University

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19726431, 27884173, 11536079, 16086317, 19339160, 33144682) -

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:3

Mar 01, 2021

PXE International

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 29, 2015

Baylor Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was found once in our laboratory in trans with a pathogenic variant [R518X] in a 39-year-old male with hereditary anemia, angioid streaks on retina, possible pseudoxanthoma elasticum, fatigue, chronic joint pain. However, variant is common, and we have identified homozygotes who do not have features of PXE. -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 01, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Pseudoxanthoma elasticum, forme fruste

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

Benign:1

Sep 29, 2021

Fulgent Genetics, Fulgent Genetics

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

0.067

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.9

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

PhyloP100

0.014

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.082

Sift

Benign

0.48

T;.

Sift4G

Benign

0.29

T;T

Polyphen

0.0

B;.

Vest4

0.056

MPC

0.085

ClinPred

0.0025

GERP RS

-1.0

Varity_R

0.055

gMVP

0.19

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0085

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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