rs397514757

Variant names:

• chr2-219218166-T-C
• rs397514757
• NM_005689.4:c.508A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005689.4(ABCB6):​c.508A>G​(p.Ser170Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ABCB6 NM_005689.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.18
• Publications: 8 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219218166-T-C is Pathogenic according to our data. Variant chr2-219218166-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 64647.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2798796). . Strength limited to SUPPORTING due to the PP5.

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.508A>G	p.Ser170Gly	missense	Exon 1 of 19	NP_005680.1	Q9NP58-1
	ABCB6	NM_001349828.2		c.508A>G	p.Ser170Gly	missense	Exon 1 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.508A>G	p.Ser170Gly	missense	Exon 1 of 19	ENSP00000265316.3	Q9NP58-1
	ENSG00000284820	ENST00000446716.5	TSL:2	n.*2281A>G		non_coding_transcript_exon	Exon 6 of 22	ENSP00000398528.1	H7C152
	ENSG00000284820	ENST00000446716.5	TSL:2	n.*2281A>G		3_prime_UTR	Exon 6 of 22	ENSP00000398528.1	H7C152

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00110 Hom.: 1

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	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Benign	1.7	L
PhyloP100		7.2
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.46
Sift	Benign	0.39	T
Sift4G	Benign	0.56	T
Polyphen		0.0010	B
Vest4		0.83
MutPred		0.36		Loss of sheet (P = 0.0043)
MVP		0.93
MPC		0.19
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
gMVP		0.61
Mutation Taster		=23/77	disease causing (ClinVar)

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: rs397514757; hg19: chr2-220082888;