chr2-219213842-G-A

Variant names:

• chr2-219213842-G-A
• rs149363094
• NM_005689.4:c.1562C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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 Likely 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
• Publications: 14 publications found

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

ENSG00000284820 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005689.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB6	NM_005689.4	MANE Select	c.1562C>T	p.Thr521Ile	missense	Exon 9 of 19	NP_005680.1
	ABCB6	NM_001349828.2		c.1424C>T	p.Thr475Ile	missense	Exon 8 of 18	NP_001336757.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB6	ENST00000265316.9	TSL:1 MANE Select	c.1562C>T	p.Thr521Ile	missense	Exon 9 of 19	ENSP00000265316.3
	ENSG00000284820	ENST00000446716.5	TSL:2	n.*3521C>T		non_coding_transcript_exon	Exon 13 of 22	ENSP00000398528.1
	ENSG00000284820	ENST00000446716.5	TSL:2	n.*3521C>T		3_prime_UTR	Exon 13 of 22	ENSP00000398528.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250912 AF XY: 0.0000147

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

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 v4.9

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
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.60	N
PhyloP100		1.8
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
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
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs149363094; hg19: chr2-220078564;