12-109088262-C-A

Variant names:

• chr12-109088262-C-A
• rs142477859
• NM_001145374.2:c.730G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145374.2(ALKBH2):​c.730G>T​(p.Val244Phe) 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 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. V244L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALKBH2 NM_001145374.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0650
• 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]

USP30 (HGNC:20065): (ubiquitin specific peptidase 30) USP30, a member of the ubiquitin-specific protease family (see USP1, MIM 603478), is a novel mitochondrial deubiquitinating (DUB) enzyme (Nakamura and Hirose, 2008 [PubMed 18287522]).[supplied by OMIM, Dec 2008]

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=0.20010746).

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.730G>T	p.Val244Phe	missense	Exon 4 of 4	NP_001138846.1	Q6NS38-1
	ALKBH2	NM_001001655.3		c.730G>T	p.Val244Phe	missense	Exon 4 of 4	NP_001001655.1	Q6NS38-1
	ALKBH2	NM_001145375.2		c.730G>T	p.Val244Phe	missense	Exon 4 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.730G>T	p.Val244Phe	missense	Exon 4 of 4	ENSP00000398181.1	Q6NS38-1
	ALKBH2	ENST00000343075.7	TSL:1	c.730G>T	p.Val244Phe	missense	Exon 4 of 4	ENSP00000343021.3	Q6NS38-1
	ALKBH2	ENST00000440112.2	TSL:1	c.*57G>T		3_prime_UTR	Exon 2 of 2	ENSP00000399820.2	Q6NS38-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726866

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111628

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.065
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Benign	0.080	T
Sift4G	Benign	0.075	T
Polyphen		0.94	P
Vest4		0.15
MutPred		0.54		Gain of methylation at K243 (P = 0.084)
MVP		0.30
MPC		0.21
ClinPred		0.90	D
GERP RS		-2.5
Varity_R		0.31
gMVP		0.61
Mutation Taster		=70/30	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: rs142477859; hg19: chr12-109526067;