2-219213842-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005689.4(ABCB6):c.1562C>G(p.Thr521Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,614,146 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T521A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0074 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 23 hom. )

Consequence

ABCB6
NM_005689.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.83

Publications

14 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007683784).

BP6

Variant 2-219213842-G-C is Benign according to our data. Variant chr2-219213842-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00742 (1130/152302) while in subpopulation AFR AF = 0.0176 (730/41560). AF 95% confidence interval is 0.0165. There are 12 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB6	NM_005689.4 link	c.1562C>G	p.Thr521Ser	missense_variant	Exon 9 of 19	ENST00000265316.9	NP_005680.1
ABCB6	NM_001349828.2 link	c.1424C>G	p.Thr475Ser	missense_variant	Exon 8 of 18		NP_001336757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCB6	ENST00000265316.9 link	c.1562C>G	p.Thr521Ser	missense_variant	Exon 9 of 19	1	NM_005689.4	ENSP00000265316.3
ENSG00000284820	ENST00000446716.5 link	n.*3521C>G		non_coding_transcript_exon_variant	Exon 13 of 22	2		ENSP00000398528.1
ENSG00000284820	ENST00000446716.5 link	n.*3521C>G		3_prime_UTR_variant	Exon 13 of 22	2		ENSP00000398528.1

Frequencies

GnomAD3 genomes

AF:

0.00742

AC:

1129

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0176

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00366

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00448

Gnomad OTH

AF:

0.00576

GnomAD2 exomes

AF:

0.00382

AC:

959

AN:

250912

AF XY:

0.00375

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00437

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00423

AC:

6190

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2979

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.0176

AC:

589

AN:

33480

American (AMR)

AF:

0.00275

AC:

123

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00398

AC:

104

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00160

AC:

138

AN:

86256

European-Finnish (FIN)

AF:

0.000862

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00431

AC:

4793

AN:

1112010

Other (OTH)

AF:

0.00584

AC:

353

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

410

820

1230

1640

2050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

384

576

768

960

<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:

0.00742

AC:

1130

AN:

152302

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

534

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0176

AC:

730

AN:

41560

American (AMR)

AF:

0.00366

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00448

AC:

305

AN:

68028

Other (OTH)

AF:

0.00617

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00481

Hom.:

Bravo

AF:

0.00858

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00385

AC:

468

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:8

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCB6: BP4, BS1, BS2 -

Mar 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Apr 18, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jan 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical 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: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

- -

Hereditary coproporphyria

Benign:1

Aug 16, 2021

Phillips Lab, Hematology, University of Utah

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.068

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.39

T;T

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

-0.14

N;.

PhyloP100

1.8

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.46

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.55

T;.

Sift4G

Benign

0.67

T;.

Polyphen

0.0

B;B

Vest4

0.72

MutPred

0.47

Gain of helix (P = 0.0425);.;

MVP

0.81

MPC

0.19

ClinPred

0.0024

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.57

Mutation Taster

=91/9

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