16-16157742-C-T

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.3803G>A(p.Arg1268Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,528 control chromosomes in the GnomAD database, including 59,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1268W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4588 hom., cov: 31)

Exomes 𝑓: 0.27 ( 54795 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:13

Conservation

PhyloP100: 0.194

Publications

72 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=4.3469667E-4).

BP6

Variant 16-16157742-C-T is Benign according to our data. Variant chr16-16157742-C-T is described in ClinVar as Benign. ClinVar VariationId is 6570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC6	NM_001171.6 link	c.3803G>A	p.Arg1268Gln	missense_variant	Exon 27 of 31	ENST00000205557.12	NP_001162.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.3803G>A	p.Arg1268Gln	missense_variant	Exon 27 of 31	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000456970.6 link	n.*812G>A		non_coding_transcript_exon_variant	Exon 25 of 29	2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 link	n.3803G>A		non_coding_transcript_exon_variant	Exon 27 of 32	5		ENSP00000483331.2	A0A8C8Q0G8
ABCC6	ENST00000456970.6 link	n.*812G>A		3_prime_UTR_variant	Exon 25 of 29	2		ENSP00000405002.2	O95255-3

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34600

AN:

151818

Hom.:

4584

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.377

Gnomad AMR

AF:

0.284

Gnomad ASJ

AF:

0.164

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.354

Gnomad MID

AF:

0.166

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.213

GnomAD2 exomes

AF:

0.250

AC:

62623

AN:

250742

AF XY:

0.247

show subpopulations

Gnomad AFR exome

AF:

0.102

Gnomad AMR exome

AF:

0.312

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.122

Gnomad FIN exome

AF:

0.346

Gnomad NFE exome

AF:

0.280

Gnomad OTH exome

AF:

0.249

GnomAD4 exome

AF:

0.268

AC:

392187

AN:

1461592

Hom.:

54795

Cov.:

AF XY:

0.266

AC XY:

193194

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0981

AC:

3284

AN:

33478

American (AMR)

AF:

0.311

AC:

13884

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4401

AN:

26132

East Asian (EAS)

AF:

0.143

AC:

5677

AN:

39700

South Asian (SAS)

AF:

0.181

AC:

15596

AN:

86244

European-Finnish (FIN)

AF:

0.339

AC:

18037

AN:

53276

Middle Eastern (MID)

AF:

0.155

AC:

892

AN:

5764

European-Non Finnish (NFE)

AF:

0.284

AC:

315750

AN:

1111904

Other (OTH)

AF:

0.243

AC:

14666

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

17248

34495

51743

68990

86238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10326

20652

30978

41304

51630

<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:

0.228

AC:

34615

AN:

151936

Hom.:

4588

Cov.:

AF XY:

0.229

AC XY:

17027

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.105

AC:

4341

AN:

41466

American (AMR)

AF:

0.284

AC:

4339

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

569

AN:

3468

East Asian (EAS)

AF:

0.124

AC:

638

AN:

5156

South Asian (SAS)

AF:

0.175

AC:

843

AN:

4808

European-Finnish (FIN)

AF:

0.354

AC:

3739

AN:

10564

Middle Eastern (MID)

AF:

0.171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.284

AC:

19310

AN:

67914

Other (OTH)

AF:

0.211

AC:

444

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1307

2615

3922

5230

6537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

358

716

1074

1432

1790

<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:

0.257

Hom.:

25222

Bravo

AF:

0.216

TwinsUK

AF:

0.283

AC:

1048

ALSPAC

AF:

0.287

AC:

1108

ESP6500AA

AF:

0.108

AC:

473

ESP6500EA

AF:

0.283

AC:

2437

ExAC

AF:

0.244

AC:

29625

Asia WGS

AF:

0.153

AC:

531

AN:

3478

EpiCase

AF:

0.262

EpiControl

AF:

0.262

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:1Benign:3

May 23, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 01, 2021

PXE International

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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: 10913334, 12928920, 21179111, 20981092, 20220177, 10811882, 27884173, 11536079, 23674961) -

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

Dec 13, 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

0.071

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.00043

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.

PhyloP100

0.19

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.9

N;.

REVEL

Benign

0.19

Sift

Benign

0.35

T;.

Sift4G

Benign

0.44

T;.

Polyphen

0.11

B;.

Vest4

0.055

MPC

0.077

ClinPred

0.0065

GERP RS

2.0

Varity_R

0.080

gMVP

0.61

Mutation Taster

=87/13

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