chr12-109088332-G-A

Variant names:

• chr12-109088332-G-A
• rs374317590
• ENST00000440112.2:c.461C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001205179.2(ALKBH2):​c.461C>T​(p.Thr154Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,614,006 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (2 hom.)
• Consequence: ALKBH2 NM_001205179.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0620

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018609881).
• BP6: Variant 12-109088332-G-A is Benign according to our data. Variant chr12-109088332-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3525726.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALKBH2	NM_001145374.2	c.660C>T	p.His220His	synonymous_variant	Exon 4 of 4	ENST00000429722.3	NP_001138846.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALKBH2	ENST00000440112.2	c.461C>T	p.Thr154Met	missense_variant	Exon 2 of 2	1		ENSP00000399820.2
ALKBH2	ENST00000429722.3	c.660C>T	p.His220His	synonymous_variant	Exon 4 of 4	5	NM_001145374.2	ENSP00000398181.1
ALKBH2	ENST00000343075.7	c.660C>T	p.His220His	synonymous_variant	Exon 4 of 4	1		ENSP00000343021.3
ALKBH2	ENST00000619381.4	c.461C>T	p.Thr154Met	missense_variant	Exon 3 of 3	5		ENSP00000478765.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000700

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251470 Hom.: 1 AF XY: 0.000140 AC XY: 19 AN XY: 135916

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461884 Hom.: 2 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727246

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74314

Gnomad4 AFR AF: 0.000700

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000310

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 20, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	1.6
DANN	Uncertain	1.0
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.53	T;.
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	-1.2	.;N
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.19
MutPred		0.28		Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);
MVP		0.45
ClinPred		0.037	T
GERP RS		-1.8

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

LitVar

Other links and lift over

dbSNP: rs374317590; hg19: chr12-109526137; COSMIC: COSV57449979; COSMIC: COSV57449979;