NM_001145374.2:c.466G>C

Variant names:

• chr12-109090022-C-G
• rs367979659
• NM_001145374.2:c.466G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001145374.2(ALKBH2):​c.466G>C​(p.Val156Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALKBH2 NM_001145374.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18
• Publications: 0 publications found

Genes affected

ALKBH2 (HGNC:32487): (alkB homolog 2, alpha-ketoglutarate dependent dioxygenase) The Escherichia coli AlkB protein protects against the cytotoxicity of methylating agents by repair of the specific DNA lesions generated in single-stranded DNA. ALKBH2 and ALKBH3 (MIM 610603) are E. coli AlkB homologs that catalyze the removal of 1-methyladenine and 3-methylcytosine (Duncan et al., 2002 [PubMed 12486230]).[supplied by OMIM, Mar 2008]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145374.2. 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
	ALKBH2	NM_001145374.2	MANE Select	c.466G>C	p.Val156Leu	missense	Exon 3 of 4	NP_001138846.1	Q6NS38-1
	ALKBH2	NM_001001655.3		c.466G>C	p.Val156Leu	missense	Exon 3 of 4	NP_001001655.1	Q6NS38-1
	ALKBH2	NM_001145375.2		c.466G>C	p.Val156Leu	missense	Exon 3 of 4	NP_001138847.1	Q6NS38-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALKBH2	ENST00000429722.3	TSL:5 MANE Select	c.466G>C	p.Val156Leu	missense	Exon 3 of 4	ENSP00000398181.1	Q6NS38-1
	ALKBH2	ENST00000343075.7	TSL:1	c.466G>C	p.Val156Leu	missense	Exon 3 of 4	ENSP00000343021.3	Q6NS38-1
	ALKBH2	ENST00000440112.2	TSL:1	c.281-1510G>C		intron	N/A	ENSP00000399820.2	Q6NS38-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.75		Gain of helix (P = 0.2294)
MVP		0.63
MPC		0.59
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.71
Mutation Taster		=29/71	disease causing

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: rs367979659; hg19: chr12-109527827;