2-219210752-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BS1_Supporting BS2

The NM_005689.4(ABCB6):c.2215C>T(p.Arg739Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000324 in 1,613,730 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R739H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: ABCB6 NM_005689.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000296 (45/152236) while in subpopulation AMR AF= 0.000654 (10/15300). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 15 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 GnomAd at 45 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB6	NM_005689.4	c.2215C>T	p.Arg739Cys	missense_variant	16/19	ENST00000265316.9
ABCB6	NM_001349828.2	c.2077C>T	p.Arg693Cys	missense_variant	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB6	ENST00000265316.9	c.2215C>T	p.Arg739Cys	missense_variant	16/19	1	NM_005689.4	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000424 AC: 105 AN: 247698 Hom.: 0 AF XY: 0.000380 AC XY: 51 AN XY: 134336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000804

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.00165

GnomAD4 exome AF: 0.000327 AC: 478 AN: 1461494 Hom.: 2 Cov.: 32 AF XY: 0.000336 AC XY: 244 AN XY: 727012

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000310

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74430

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 739 of the ABCB6 protein (p.Arg739Cys). This variant is present in population databases (rs141840760, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ABCB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 993667). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 23, 2020	- -

ABCB6-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2023

The ABCB6 c.2215C>T variant is predicted to result in the amino acid substitution p.Arg739Cys. This variant has been reported along with two variants in the SPTA1 gene in an individual with an erythrocyte disorder (Andolfo et al. 2021. PubMed ID: 34201899). This variant is reported in 0.11% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-220075474-G-A), which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, 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	0.78
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.94
MVP		0.95
MPC		0.95
ClinPred		0.50	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.91

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

Other links and lift over

dbSNP: rs141840760; hg19: chr2-220075474; COSMIC: COSV54694962; COSMIC: COSV54694962;