rs41278174

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001171.6(ABCC6):c.3190C>T(p.Arg1064Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,760 control chromosomes in the GnomAD database, including 587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1064Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 33)

Exomes 𝑓: 0.025 ( 553 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:16

Conservation

PhyloP100: 3.53

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 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, 5 uncertain in NM_001171.6

BP4

Computational evidence support a benign effect (MetaRNN=0.010730177).

BP6

Variant 16-16165739-G-A is Benign according to our data. Variant chr16-16165739-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 433305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16165739-G-A is described in Lovd as [Benign]. Variant chr16-16165739-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0175 (2670/152336) while in subpopulation SAS AF = 0.0317 (153/4828). AF 95% confidence interval is 0.0276. There are 34 homozygotes in GnomAd4. There are 1358 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCC6	NM_001171.6 link	c.3190C>T	p.Arg1064Trp	missense_variant	Exon 23 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 link	c.2848C>T	p.Arg950Trp	missense_variant	Exon 23 of 31		NP_001338729.1
ABCC6	NR_147784.1 link	n.3052C>T		non_coding_transcript_exon_variant	Exon 22 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.3190C>T	p.Arg1064Trp	missense_variant	Exon 23 of 31	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000456970.6 link	n.*399C>T		non_coding_transcript_exon_variant	Exon 22 of 29	2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 link	n.3190C>T		non_coding_transcript_exon_variant	Exon 23 of 32	5		ENSP00000483331.2	A0A8C8Q0G8
ABCC6	ENST00000456970.6 link	n.*399C>T		3_prime_UTR_variant	Exon 22 of 29	2		ENSP00000405002.2	O95255-3

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2669

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00432

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00936

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0207

AC:

5197

AN:

251186

AF XY:

0.0216

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00867

Gnomad ASJ exome

AF:

0.0219

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0356

Gnomad NFE exome

AF:

0.0244

Gnomad OTH exome

AF:

0.0196

GnomAD4 exome

AF:

0.0248

AC:

36279

AN:

1461424

Hom.:

553

Cov.:

AF XY:

0.0250

AC XY:

18157

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00341

AC:

114

AN:

33480

Gnomad4 AMR exome

AF:

0.00912

AC:

408

AN:

44722

Gnomad4 ASJ exome

AF:

0.0209

AC:

546

AN:

26136

Gnomad4 EAS exome

AF:

0.000101

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0311

AC:

2683

AN:

86258

Gnomad4 FIN exome

AF:

0.0340

AC:

1803

AN:

52964

Gnomad4 NFE exome

AF:

0.0262

AC:

29159

AN:

1112006

Gnomad4 Remaining exome

AF:

0.0242

AC:

1460

AN:

60390

Heterozygous variant carriers

2382

4763

7145

9526

11908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

1102

2204

3306

4408

5510

<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:

0.0175

AC:

2670

AN:

152336

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

1358

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00430

AC:

0.00430495

AN:

0.00430495

Gnomad4 AMR

AF:

0.00935

AC:

0.00934518

AN:

0.00934518

Gnomad4 ASJ

AF:

0.0236

AC:

0.0236175

AN:

0.0236175

Gnomad4 EAS

AF:

0.000580

AC:

0.000579598

AN:

0.000579598

Gnomad4 SAS

AF:

0.0317

AC:

0.0316901

AN:

0.0316901

Gnomad4 FIN

AF:

0.0364

AC:

0.0363534

AN:

0.0363534

Gnomad4 NFE

AF:

0.0246

AC:

0.0246039

AN:

0.0246039

Gnomad4 OTH

AF:

0.0137

AC:

0.0137051

AN:

0.0137051

Heterozygous variant carriers

139

277

416

554

693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0224

Hom.:

157

Bravo

AF:

0.0148

TwinsUK

AF:

0.0254

AC:

ALSPAC

AF:

0.0246

AC:

ESP6500AA

AF:

0.00410

AC:

ESP6500EA

AF:

0.0243

AC:

209

ExAC

AF:

0.0205

AC:

2488

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCC6: BS1, BS2 -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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: 31456290, 16086317, 25264593) -

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:1Benign:3

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Oct 05, 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

- -

Jun 06, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Clinical Genetics, Academic Medical Center

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

- -

May 04, 2022

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:2

Nov 12, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

0.15

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.1

M;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.8

D;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.010

D;.

Sift4G

Uncertain

0.026

D;.

Polyphen

1.0

D;.

Vest4

0.25

MPC

0.38

ClinPred

0.041

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.55

Mutation Taster

=89/11

disease causing (ClinVar)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over