chr2-219210799-C-T

Position:

chr2-219210799-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_005689.4(ABCB6):c.2168G>A(p.Arg723Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,613,838 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

ABCB6
NM_005689.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:4

Conservation

PhyloP100: 6.02

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 links:

ENSG00000284820 (HGNC:):

ENSG00000284820 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000736 (112/152232) while in subpopulation NFE AF= 0.00134 (91/68022). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 112 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB6	NM_005689.4 linkuse as main transcript	c.2168G>A	p.Arg723Gln	missense_variant	16/19	ENST00000265316.9	NP_005680.1	Q9NP58-1
ABCB6	NM_001349828.2 linkuse as main transcript	c.2030G>A	p.Arg677Gln	missense_variant	15/18		NP_001336757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCB6	ENST00000265316.9 linkuse as main transcript	c.2168G>A	p.Arg723Gln	missense_variant	16/19	1	NM_005689.4	ENSP00000265316.3	Q9NP58-1
ENSG00000284820	ENST00000446716.5 linkuse as main transcript	n.*3952G>A		non_coding_transcript_exon_variant	19/22	2		ENSP00000398528.1	H7C152
ENSG00000284820	ENST00000446716.5 linkuse as main transcript	n.*3952G>A		3_prime_UTR_variant	19/22	2		ENSP00000398528.1	H7C152

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000766

AC:

191

AN:

249416

Hom.:

AF XY:

0.000859

AC XY:

116

AN XY:

135102

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.00113

AC:

1646

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

826

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00108

Gnomad4 FIN exome

AF:

0.000263

Gnomad4 NFE exome

AF:

0.00131

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000736

AC:

112

AN:

152232

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000865

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000832

AC:

101

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00172

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2023	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 218181). This missense change has been observed in individual(s) with familial pseudohyperkalemia (PMID: 24947683, 27151991). This variant is present in population databases (rs148211042, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 723 of the ABCB6 protein (p.Arg723Gln). Experimental studies have shown that this missense change affects ABCB6 function (PMID: 27151991). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Familial pseudohyperkalemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2014

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

ABCB6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2024

The ABCB6 c.2168G>A variant is predicted to result in the amino acid substitution p.Arg723Gln. This variant has been reported in multiple unrelated individuals with pseudohyperkalemia and was reported to segregate with disease in four affected individuals in a three generation pedigree (Bawazir et al. 2014. PubMed ID: 24947683; Andolfo et al. 2016. PubMed ID: 27151991). Functional studies found this variant results in increased potassium efflux (Andolfo et al. 2016. PubMed ID: 27151991). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.59

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.3

L;.

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.8

D;.

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.94

MVP

0.94

MPC

0.87

ClinPred

0.19

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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