rs58073789

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001171.6(ABCC6):c.2171G>A(p.Arg724Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,614,154 control chromosomes in the GnomAD database, including 282 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. R724L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 27 hom., cov: 32)

Exomes 𝑓: 0.015 ( 255 hom. )

Consequence

ABCC6
NM_001171.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0630

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 made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain ABC transporter 1 (size 224) in uniprot entity MRP6_HUMAN there are 31 pathogenic changes around while only 5 benign (86%) in NM_001171.6

BP4

Computational evidence support a benign effect (MetaRNN=0.008916229).

BP6

Variant 16-16182488-C-T is Benign according to our data. Variant chr16-16182488-C-T is described in ClinVar as [Benign]. Clinvar id is 433261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16182488-C-T is described in Lovd as [Benign]. Variant chr16-16182488-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0167 (2544/152300) while in subpopulation SAS AF= 0.0366 (177/4830). AF 95% confidence interval is 0.0322. There are 27 homozygotes in gnomad4. There are 1190 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCC6	NM_001171.6 link	c.2171G>A	p.Arg724Lys	missense_variant	Exon 17 of 31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 link	c.1829G>A	p.Arg610Lys	missense_variant	Exon 17 of 31		NP_001338729.1
ABCC6	NR_147784.1 link	n.2208G>A		non_coding_transcript_exon_variant	Exon 17 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCC6	ENST00000205557.12 link	c.2171G>A	p.Arg724Lys	missense_variant	Exon 17 of 31	1	NM_001171.6	ENSP00000205557.7	O95255-1
ABCC6	ENST00000456970.6 link	n.2171G>A		non_coding_transcript_exon_variant	Exon 17 of 29	2		ENSP00000405002.2	O95255-3
ABCC6	ENST00000622290.5 link	n.2171G>A		non_coding_transcript_exon_variant	Exon 17 of 32	5		ENSP00000483331.2	A0A8C8Q0G8

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2542

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0282

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0368

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0133

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0137

AC:

3453

AN:

251438

Hom.:

AF XY:

0.0152

AC XY:

2067

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0269

Gnomad AMR exome

AF:

0.00570

Gnomad ASJ exome

AF:

0.0145

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0362

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.0148

AC:

21630

AN:

1461854

Hom.:

255

Cov.:

AF XY:

0.0155

AC XY:

11283

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0295

Gnomad4 AMR exome

AF:

0.00555

Gnomad4 ASJ exome

AF:

0.0130

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0376

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.0140

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0167

AC:

2544

AN:

152300

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1190

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0282

Gnomad4 AMR

AF:

0.0121

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0366

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.0133

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0141

Hom.:

Bravo

AF:

0.0174

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.0289

AC:

127

ESP6500EA

AF:

0.0122

AC:

105

ExAC

AF:

0.0150

AC:

1822

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0168

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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

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

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

- -

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

0.071

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

1.1

DANN

Benign

0.38

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.0089

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.10

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.68

N;.

REVEL

Benign

0.23

Sift

Benign

0.83

T;.

Sift4G

Benign

0.88

T;T

Polyphen

0.013

B;.

Vest4

0.072

MPC

0.069

ClinPred

0.00052

GERP RS

-2.5

Varity_R

0.12

gMVP

0.51

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