rs149363094

Positions:

• chr2-219213842-G-A
• chr2-219213842-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005689.4(ABCB6):​c.1562C>T​(p.Thr521Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T521S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCB6 NM_005689.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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]

ENSG00000284820 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1674026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB6	NM_005689.4	c.1562C>T	p.Thr521Ile	missense_variant	9/19	ENST00000265316.9	NP_005680.1
ABCB6	NM_001349828.2	c.1424C>T	p.Thr475Ile	missense_variant	8/18		NP_001336757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB6	ENST00000265316.9	c.1562C>T	p.Thr521Ile	missense_variant	9/19	1	NM_005689.4	ENSP00000265316.3
ENSG00000284820	ENST00000446716.5	n.*3521C>T		non_coding_transcript_exon_variant	13/22	2		ENSP00000398528.1
ENSG00000284820	ENST00000446716.5	n.*3521C>T		3_prime_UTR_variant	13/22	2		ENSP00000398528.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250912 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.60	N;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.12	N;.
REVEL	Benign	0.27
Sift	Benign	0.21	T;.
Sift4G	Benign	0.36	T;.
Polyphen		0.0010	B;B
Vest4		0.36
MutPred		0.46		Gain of helix (P = 0.027);.;
MVP		0.85
MPC		0.23
ClinPred		0.095	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.62

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: rs149363094; hg19: chr2-220078564;