rs41278174

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.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 (★★).

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:15

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 made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain ABC transmembrane type-1 2 (size 281) in uniprot entity MRP6_HUMAN there are 30 pathogenic changes around while only 5 benign (86%) 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

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

GnomAD3 exomes

AF:

0.0207

AC:

5197

AN:

251186

Hom.:

AF XY:

0.0216

AC XY:

2940

AN XY:

135888

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 SAS exome

AF:

0.0311

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

Gnomad4 AMR exome

AF:

0.00912

Gnomad4 ASJ exome

AF:

0.0209

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0311

Gnomad4 FIN exome

AF:

0.0340

Gnomad4 NFE exome

AF:

0.0262

Gnomad4 OTH exome

AF:

0.0242

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

Gnomad4 AMR

AF:

0.00935

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0317

Gnomad4 FIN

AF:

0.0364

Gnomad4 NFE

AF:

0.0246

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0230

Hom.:

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31456290, 16086317, 25264593) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	ABCC6: BS1, BS2 -

Autosomal recessive inherited pseudoxanthoma elasticum

Pathogenic:1Benign:3

Benign, no assertion criteria provided	research	PXE International	Oct 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Pseudoxanthoma elasticum, forme fruste

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Arterial calcification, generalized, of infancy, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 12, 2021

- -

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

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