rs78629019

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001171.6(ABCC6):c.793A>G(p.Arg265Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0666 in 151,816 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.067 ( 358 hom., cov: 30)

Exomes 𝑓: 0.037 ( 3822 hom. )

Failed GnomAD Quality Control

Consequence

ABCC6
NM_001171.6 missense, splice_region

Scores

Splicing: ADA: 0.008483

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0140

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022835135).

BP6

Variant 16-16208729-T-C is Benign according to our data. Variant chr16-16208729-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 143120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-16208729-T-C is described in Lovd as [Benign]. Variant chr16-16208729-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0784 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.793A>G	p.Arg265Gly	missense_variant, splice_region_variant	7/31	ENST00000205557.12	NP_001162.5
ABCC6	NM_001351800.1 linkuse as main transcript	c.451A>G	p.Arg151Gly	missense_variant, splice_region_variant	7/31		NP_001338729.1
ABCC6	NR_147784.1 linkuse as main transcript	n.830A>G		splice_region_variant, non_coding_transcript_exon_variant	7/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC6	ENST00000205557.12 linkuse as main transcript	c.793A>G	p.Arg265Gly	missense_variant, splice_region_variant	7/31	1	NM_001171.6	ENSP00000205557	P1	O95255-1

Frequencies

GnomAD3 genomes

AF:

0.0666

AC:

10110

AN:

151698

Hom.:

359

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0599

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.0601

Gnomad ASJ

AF:

0.0709

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.0264

Gnomad FIN

AF:

0.0448

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0802

Gnomad OTH

AF:

0.0685

GnomAD3 exomes

AF:

0.0427

AC:

10355

AN:

242738

Hom.:

511

AF XY:

0.0431

AC XY:

5647

AN XY:

131142

show subpopulations

Gnomad AFR exome

AF:

0.0482

Gnomad AMR exome

AF:

0.0249

Gnomad ASJ exome

AF:

0.0312

Gnomad EAS exome

AF:

0.0231

Gnomad SAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.0378

Gnomad NFE exome

AF:

0.0603

Gnomad OTH exome

AF:

0.0465

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0366

AC:

49797

AN:

1360146

Hom.:

3822

Cov.:

AF XY:

0.0372

AC XY:

25224

AN XY:

678628

show subpopulations

Gnomad4 AFR exome

AF:

0.0333

Gnomad4 AMR exome

AF:

0.0269

Gnomad4 ASJ exome

AF:

0.0501

Gnomad4 EAS exome

AF:

0.0427

Gnomad4 SAS exome

AF:

0.0199

Gnomad4 FIN exome

AF:

0.0479

Gnomad4 NFE exome

AF:

0.0371

Gnomad4 OTH exome

AF:

0.0409

GnomAD4 genome

AF:

0.0666

AC:

10108

AN:

151816

Hom.:

358

Cov.:

AF XY:

0.0644

AC XY:

4777

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.0598

Gnomad4 AMR

AF:

0.0600

Gnomad4 ASJ

AF:

0.0709

Gnomad4 EAS

AF:

0.0330

Gnomad4 SAS

AF:

0.0262

Gnomad4 FIN

AF:

0.0448

Gnomad4 NFE

AF:

0.0802

Gnomad4 OTH

AF:

0.0678

Alfa

AF:

0.0763

Hom.:

114

Bravo

AF:

0.0681

ExAC

AF:

0.0600

AC:

7282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 19726431, 27884173, 11536079, 16086317, 19339160, 33144682) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

Autosomal recessive inherited pseudoxanthoma elasticum

Benign:3

Benign, criteria provided, single submitter	research	PXE International	Mar 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 29, 2015	This variant was found once in our laboratory in trans with a pathogenic variant [R518X] in a 39-year-old male with hereditary anemia, angioid streaks on retina, possible pseudoxanthoma elasticum, fatigue, chronic joint pain. However, variant is common, and we have identified homozygotes who do not have features of PXE. -

not specified

Benign:2

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	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Sep 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

1.9

DANN

Benign

0.74

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

N;.

REVEL

Benign

0.082

Sift

Benign

0.48

T;.

Sift4G

Benign

0.29

T;T

Polyphen

0.0

B;.

Vest4

0.056

MPC

0.085

ClinPred

0.0025

GERP RS

-1.0

Varity_R

0.055

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0085

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: -1

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