chr2-206750958-G-C

Variant names:

• chr2-206750958-G-C
• rs546473860
• NM_001039845.3:c.1028C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001039845.3(MDH1B):​c.1028C>G​(p.Pro343Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P343L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDH1B NM_001039845.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 0 publications found

Genes affected

MDH1B (HGNC:17836): (malate dehydrogenase 1B) Predicted to enable L-malate dehydrogenase activity. Predicted to be involved in NADH metabolic process; dicarboxylic acid metabolic process; and tricarboxylic acid cycle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40630394).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039845.3. 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
	MDH1B	NM_001039845.3	MANE Select	c.1028C>G	p.Pro343Arg	missense	Exon 6 of 12	NP_001034934.1	Q5I0G3-1
	MDH1B	NM_001282940.2		c.1028C>G	p.Pro343Arg	missense	Exon 6 of 12	NP_001269869.1	Q5I0G3-2
	MDH1B	NM_001330223.2		c.734C>G	p.Pro245Arg	missense	Exon 5 of 11	NP_001317152.1	C9JER5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDH1B	ENST00000374412.8	TSL:1 MANE Select	c.1028C>G	p.Pro343Arg	missense	Exon 6 of 12	ENSP00000363533.3	Q5I0G3-1
	MDH1B	ENST00000432911.5	TSL:1	n.414-1775C>G		intron	N/A	ENSP00000392464.1	Q5I0G3-3
	MDH1B	ENST00000454776.6	TSL:2	c.1028C>G	p.Pro343Arg	missense	Exon 6 of 12	ENSP00000389916.2	Q5I0G3-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.0
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.19
Sift	Uncertain	0.019	D
Sift4G	Benign	0.086	T
Polyphen		0.42	B
Vest4		0.45
MutPred		0.44		Gain of MoRF binding (P = 0.0391)
MVP		0.45
MPC		0.21
ClinPred		0.94	D
GERP RS		4.1
Varity_R		0.16
gMVP		0.82
Mutation Taster		=93/7	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: rs546473860; hg19: chr2-207615682;