NM_001145374.2:c.660C>A

Variant names:

• chr12-109088332-G-T
• rs374317590
• NM_001145374.2:c.660C>A

Variant summary

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

The NM_001145374.2(ALKBH2):​c.660C>A​(p.His220Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H220H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: ALKBH2 NM_001145374.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.660C>A	p.His220Gln	missense	Exon 4 of 4	NP_001138846.1	Q6NS38-1
	ALKBH2	NM_001001655.3		c.660C>A	p.His220Gln	missense	Exon 4 of 4	NP_001001655.1	Q6NS38-1
	ALKBH2	NM_001145375.2		c.660C>A	p.His220Gln	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.660C>A	p.His220Gln	missense	Exon 4 of 4	ENSP00000398181.1	Q6NS38-1
	ALKBH2	ENST00000343075.7	TSL:1	c.660C>A	p.His220Gln	missense	Exon 4 of 4	ENSP00000343021.3	Q6NS38-1
	ALKBH2	ENST00000440112.2	TSL:1	c.461C>A	p.Thr154Lys	missense	Exon 2 of 2	ENSP00000399820.2	Q6NS38-2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251470 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727246

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: 86258

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53412

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

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1112010

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.35	T
PhyloP100		-0.062
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.25
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.51		Gain of MoRF binding (P = 0.1015)
MVP		0.32
MPC		0.61
ClinPred		0.35	T
GERP RS		-1.8
Varity_R		0.87
gMVP		0.69
Mutation Taster		=49/51	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: rs374317590; hg19: chr12-109526137;