rs149202834

Positions:

• chr2-219217783-G-A
• chr2-219217783-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005689.4(ABCB6):​c.574C>T​(p.Arg192Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00183 in 1,613,266 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts 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. R192Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: ABCB6 NM_005689.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:6 O:1
• Conservation: PhyloP100: 4.89

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17885265).
• BP6: Variant 2-219217783-G-A is Benign according to our data. Variant chr2-219217783-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 217872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-219217783-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (240/152076) while in subpopulation NFE AF= 0.00304 (207/67998). AF 95% confidence interval is 0.0027. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 240 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB6	NM_005689.4	c.574C>T	p.Arg192Trp	missense_variant	2/19	ENST00000265316.9
ABCB6	NM_001349828.2	c.549+342C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB6	ENST00000265316.9	c.574C>T	p.Arg192Trp	missense_variant	2/19	1	NM_005689.4	P1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 151962 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00157 AC: 392 AN: 249650 Hom.: 0 AF XY: 0.00153 AC XY: 206 AN XY: 135066

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000500

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00186 AC: 2716 AN: 1461190 Hom.: 8 Cov.: 33 AF XY: 0.00190 AC XY: 1382 AN XY: 726942

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000427

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00184

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152076 Hom.: 1 Cov.: 31 AF XY: 0.00139 AC XY: 103 AN XY: 74352

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00217 Hom.: 1

Bravo AF: 0.00128

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00183 AC: 222

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ABCB6: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Acute intermittent porphyria Benign:1

Benign, criteria provided, single submitter

clinical testing

Phillips Lab, Hematology, University of Utah

Aug 16, 2021

- -

Variegate porphyria Benign:1

Benign, criteria provided, single submitter

clinical testing

Phillips Lab, Hematology, University of Utah

Aug 16, 2021

- -

Protoporphyria, erythropoietic, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Phillips Lab, Hematology, University of Utah

Aug 16, 2021

- -

Hereditary coproporphyria Benign:1

Benign, criteria provided, single submitter

clinical testing

Phillips Lab, Hematology, University of Utah

Aug 16, 2021

- -

Langereis blood group Other:1

Affects, no assertion criteria provided

literature only

OMIM

Feb 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.98
MPC		0.81
ClinPred		0.078	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs149202834; hg19: chr2-220082505;