7-2235297-C-G

Variant names:

• chr7-2235297-C-G
• rs139361869
• NM_013393.3:c.566G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_013393.3(MRM2):​c.566G>C​(p.Gly189Ala) 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. 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. G189R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MRM2 NM_013393.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43
• Publications: 0 publications found

Genes affected

MRM2 (HGNC:16352): (mitochondrial rRNA methyltransferase 2) The protein encoded by this gene is a member of the S-adenosylmethionine-binding protein family. It is a nucleolar protein and it may be involved in the processing and modification of rRNA. This gene has been suggested to be involved in cell cycle control and DNA repair. [provided by RefSeq, Jul 2008]

MRM2 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 17

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000286192 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-2235298-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 689394.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013393.3. 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
	MRM2	NM_013393.3	MANE Select	c.566G>C	p.Gly189Ala	missense	Exon 3 of 3	NP_037525.1	Q9UI43

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRM2	ENST00000242257.14	TSL:1 MANE Select	c.566G>C	p.Gly189Ala	missense	Exon 3 of 3	ENSP00000242257.8	Q9UI43
	MRM2	ENST00000486040.1	TSL:1	n.*1021G>C		non_coding_transcript_exon	Exon 4 of 4	ENSP00000498090.1	A0A3B3ITW8
	ENSG00000286192	ENST00000651235.1		n.*1021G>C		non_coding_transcript_exon	Exon 4 of 24	ENSP00000498895.1	A0A3B3ITW8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.71	D
PhyloP100		7.4
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.82
Sift	Benign	0.32	T
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.94
MutPred		0.93		Gain of catalytic residue at G189 (P = 0.0763)
MVP		0.88
MPC		0.76
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.84
Mutation Taster		=13/87	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: rs139361869; hg19: chr7-2274932;