rs397514758

Variant names:

• chr2-219213310-C-T
• rs397514758
• NM_005689.4:c.1736G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005689.4(ABCB6):​c.1736G>A​(p.Gly579Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCB6 NM_005689.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.71
• Publications: 9 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, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• 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), G2P, ClinGen

ENSG00000284820 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-219213310-C-T is Pathogenic according to our data. Variant chr2-219213310-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 64648.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB6	NM_005689.4	MANE Select	c.1736G>A	p.Gly579Glu	missense	Exon 12 of 19	NP_005680.1	Q9NP58-1
	ABCB6	NM_001349828.2		c.1598G>A	p.Gly533Glu	missense	Exon 11 of 18	NP_001336757.1	Q9NP58-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCB6	ENST00000265316.9	TSL:1 MANE Select	c.1736G>A	p.Gly579Glu	missense	Exon 12 of 19	ENSP00000265316.3	Q9NP58-1
	ENSG00000284820	ENST00000446716.5	TSL:2	n.*3695G>A		non_coding_transcript_exon	Exon 16 of 22	ENSP00000398528.1	H7C152
	ENSG00000284820	ENST00000446716.5	TSL:2	n.*3695G>A		3_prime_UTR	Exon 16 of 22	ENSP00000398528.1	H7C152

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461752 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727196

⚠️ 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: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Dyschromatosis universalis hereditaria 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.36
Sift	Benign	0.039	D
Sift4G	Uncertain	0.043	D
Polyphen		0.57	P
Vest4		0.77
MutPred		0.48		Gain of solvent accessibility (P = 0.012)
MVP		0.86
MPC		0.28
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.34
gMVP		0.89
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.66		Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397514758; hg19: chr2-220078032;