11-62666998-G-C

Position:

• chr11-62666998-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001043229.2(CSKMT):​c.670G>C​(p.Gly224Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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: CSKMT NM_001043229.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.06

Genes affected

CSKMT (HGNC:33113): (citrate synthase lysine methyltransferase) Enables protein-lysine N-methyltransferase activity. Involved in peptidyl-lysine dimethylation; peptidyl-lysine monomethylation; and peptidyl-lysine trimethylation. Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

LBHD1 (HGNC:28351): (LBH domain containing 1) This gene shares three exons in common with another gene, chromosome 11 open reading frame 98 (GeneID:102288414), but the encoded protein uses a reading frame that is different from that of the chromosome 11 open reading frame 98 gene. [provided by RefSeq, Nov 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSKMT	NM_001043229.2	c.670G>C	p.Gly224Arg	missense_variant	3/3	ENST00000532971.2	NP_001036694.1
LBHD1	NM_024099.5	c.538+525C>G		intron_variant		ENST00000354588.8	NP_077004.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSKMT	ENST00000532971.2	c.670G>C	p.Gly224Arg	missense_variant	3/3	2	NM_001043229.2	ENSP00000431287	P1
LBHD1	ENST00000354588.8	c.538+525C>G		intron_variant		1	NM_024099.5	ENSP00000346600	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jun 10, 2024

The c.670G>C (p.G224R) alteration is located in exon 3 (coding exon 2) of the METTL12 gene. This alteration results from a G to C substitution at nucleotide position 670, causing the glycine (G) at amino acid position 224 to be replaced by an arginine (R). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.64		Loss of catalytic residue at Q221 (P = 0.1811);
MVP		0.68
MPC		0.22
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.34
gMVP		0.75

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: chr11-62434470;