rs2238472

Positions:

chr16-16157742-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000205557.12(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. 14/20 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. R1268W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4588 hom., cov: 31)

Exomes 𝑓: 0.27 ( 54795 hom. )

Consequence

ABCC6
ENST00000205557.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.194

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 2 (size 234) in uniprot entity MRP6_HUMAN there are 72 pathogenic changes around while only 8 benign (90%) in ENST00000205557.12

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 id is 6570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16157742-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein
ABCC6	NM_001171.6 linkuse as main transcript	c.3803G>A	p.Arg1268Gln	missense_variant	27/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.3461G>A	p.Arg1154Gln	missense_variant	27/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.3465G>A		non_coding_transcript_exon_variant	25/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.3803G>A	p.Arg1268Gln	missense_variant	27/31	1	NM_001171.6	ENSP00000205557	P1	O95255-1
ABCC6	ENST00000622290.5 linkuse as main transcript	c.3803G>A	p.Arg1268Gln	missense_variant, NMD_transcript_variant	27/32	5		ENSP00000483331
ABCC6	ENST00000456970.6 linkuse as main transcript	c.*812G>A		3_prime_UTR_variant, NMD_transcript_variant	25/29	2		ENSP00000405002		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

GnomAD3 exomes

AF:

0.250

AC:

62623

AN:

250742

Hom.:

8569

AF XY:

0.247

AC XY:

33502

AN XY:

135606

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 SAS exome

AF:

0.181

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

Gnomad4 AFR exome

AF:

0.0981

Gnomad4 AMR exome

AF:

0.311

Gnomad4 ASJ exome

AF:

0.168

Gnomad4 EAS exome

AF:

0.143

Gnomad4 SAS exome

AF:

0.181

Gnomad4 FIN exome

AF:

0.339

Gnomad4 NFE exome

AF:

0.284

Gnomad4 OTH exome

AF:

0.243

GnomAD4 genome

AF:

0.228

AC:

34615

AN:

151936

Hom.:

4588

Cov.:

AF XY:

0.229

AC XY:

17027

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.284

Gnomad4 ASJ

AF:

0.164

Gnomad4 EAS

AF:

0.124

Gnomad4 SAS

AF:

0.175

Gnomad4 FIN

AF:

0.354

Gnomad4 NFE

AF:

0.284

Gnomad4 OTH

AF:

0.211

Alfa

AF:

0.261

Hom.:

14127

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

Benign, criteria provided, single submitter	research	PXE International	Mar 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 23, 2000	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 10913334, 12928920, 21179111, 20981092, 20220177, 10811882, 27884173, 11536079, 23674961) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 13, 2021

- -

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

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;.

MutationTaster

Benign

0.036

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

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