2-219217782-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005689.4(ABCB6):c.575G>A(p.Arg192Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00368 in 1,613,524 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0038 ( 16 hom. )

Consequence

ABCB6
NM_005689.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 5.42

Publications

18 publications found

Variant links:

Genes affected

ABCB6 (HGNC:47): (ATP binding cassette subfamily B member 6 (LAN blood group)) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. ABC proteins transport various molecules across extra- and intra-cellular membranes. This protein is a member of the heavy metal importer subfamily and plays a role in porphyrin transport. This gene is the molecular basis of the Langereis (Lan) blood group antigen and mutations in this gene underlie familial pseudohyperkalemia and dyschromatosis universalis hereditaria. [provided by RefSeq, Mar 2017]

ABCB6 Gene-Disease associations (from GenCC):

dyschromatosis universalis hereditaria 3
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
dyschromatosis universalis hereditaria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial pseudohyperkalemia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
microphthalmia, isolated, with coloboma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
microphthalmia, isolated, with coloboma 7
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ABCB6 links:

ENSG00000284820 (HGNC:):

ENSG00000284820 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027407736).

BP6

Variant 2-219217782-C-T is Benign according to our data. Variant chr2-219217782-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68473.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.003 (456/152234) while in subpopulation NFE AF = 0.00454 (309/68002). AF 95% confidence interval is 0.00413. There are 0 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 456 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB6	NM_005689.4 link	c.575G>A	p.Arg192Gln	missense_variant	Exon 2 of 19	ENST00000265316.9	NP_005680.1
ABCB6	NM_001349828.2 link	c.549+343G>A		intron_variant	Intron 1 of 17		NP_001336757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCB6	ENST00000265316.9 link	c.575G>A	p.Arg192Gln	missense_variant	Exon 2 of 19	1	NM_005689.4	ENSP00000265316.3
ENSG00000284820	ENST00000446716.5 link	n.*2348G>A		non_coding_transcript_exon_variant	Exon 7 of 22	2		ENSP00000398528.1
ENSG00000284820	ENST00000446716.5 link	n.*2348G>A		3_prime_UTR_variant	Exon 7 of 22	2		ENSP00000398528.1

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

456

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00454

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00345

AC:

864

AN:

250726

AF XY:

0.00345

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.00825

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00194

Gnomad NFE exome

AF:

0.00445

Gnomad OTH exome

AF:

0.00639

GnomAD4 exome

AF:

0.00375

AC:

5485

AN:

1461290

Hom.:

Cov.:

AF XY:

0.00369

AC XY:

2681

AN XY:

726986

show subpopulations

African (AFR)

AF:

0.000479

AC:

AN:

33398

American (AMR)

AF:

0.00420

AC:

187

AN:

44548

Ashkenazi Jewish (ASJ)

AF:

0.00758

AC:

198

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000940

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00223

AC:

119

AN:

53352

Middle Eastern (MID)

AF:

0.00937

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00412

AC:

4578

AN:

1111854

Other (OTH)

AF:

0.00416

AC:

251

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

314

627

941

1254

1568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00300

AC:

456

AN:

152234

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41540

American (AMR)

AF:

0.00320

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00635

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00124

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00454

AC:

309

AN:

68002

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00449

Hom.:

Bravo

AF:

0.00311

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00342

AC:

415

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00539

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in association with multiple phenotypes including various anemias, stomatocytosis, porphyria, coloboma, or language impairment (PMID: 27507172, 29396846, 35320338, 30653986, 24281366, 36695705, 28440294); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25360778, 27507172, 24281366, 29396846, 36695705, 35320338, 28440294, 30653986, 34724702, 38557323) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCB6: BS2 -

Microphthalmia, isolated, with coloboma 7

Uncertain:1Benign:1

Mar 30, 2012

Eye Genetics Research Group, Children's Medical Research Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Dr.Nikuei Genetic Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Acute intermittent porphyria

Benign:1

Aug 16, 2021

Phillips Lab, Hematology, University of Utah

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Variegate porphyria

Benign:1

Aug 16, 2021

Phillips Lab, Hematology, University of Utah

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCB6-related disorder

Benign:1

Jun 25, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Protoporphyria, erythropoietic, 1

Benign:1

Aug 16, 2021

Phillips Lab, Hematology, University of Utah

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

0.17

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.027

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

1.8

PhyloP100

5.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.017

Polyphen

0.98

Vest4

0.78

MVP

0.97

MPC

0.69

ClinPred

0.041

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.85

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over