12-109088465-C-T

Position:

• chr12-109088465-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145374.2(ALKBH2):​c.527G>A​(p.Arg176Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign 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: 1.72

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053095162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALKBH2	NM_001145374.2	c.527G>A	p.Arg176Lys	missense_variant	4/4	ENST00000429722.3	NP_001138846.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALKBH2	ENST00000429722.3	c.527G>A	p.Arg176Lys	missense_variant	4/4	5	NM_001145374.2	ENSP00000398181.1
ALKBH2	ENST00000343075.7	c.527G>A	p.Arg176Lys	missense_variant	4/4	1		ENSP00000343021.3
ALKBH2	ENST00000440112.2	c.328G>A	p.Glu110Lys	missense_variant	2/2	1		ENSP00000399820.2
ALKBH2	ENST00000619381.4	c.328G>A	p.Glu110Lys	missense_variant	3/3	5		ENSP00000478765.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The c.527G>A (p.R176K) alteration is located in exon 4 (coding exon 3) of the ALKBH2 gene. This alteration results from a G to A substitution at nucleotide position 527, causing the arginine (R) at amino acid position 176 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.53	T;.
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	0.79	.;N
REVEL	Benign	0.058
Sift	Benign	0.31	.;T
Sift4G	Benign	0.18	T;T
Vest4		0.33
MutPred		0.44		Gain of methylation at E110 (P = 0.0067);Gain of methylation at E110 (P = 0.0067);
MVP		0.055
ClinPred		0.50	D
GERP RS		4.9

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-109526270;