2-206746361-C-T

Variant names:

• chr2-206746361-C-T
• NM_001039845.3:c.1282G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039845.3(MDH1B):​c.1282G>A​(p.Val428Met) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDH1B NM_001039845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0880
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15453827).

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.1282G>A	p.Val428Met	missense	Exon 8 of 12	NP_001034934.1	Q5I0G3-1
	MDH1B	NM_001282940.2		c.1282G>A	p.Val428Met	missense	Exon 8 of 12	NP_001269869.1	Q5I0G3-2
	MDH1B	NM_001330223.2		c.988G>A	p.Val330Met	missense	Exon 7 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.1282G>A	p.Val428Met	missense	Exon 8 of 12	ENSP00000363533.3	Q5I0G3-1
	MDH1B	ENST00000432911.5	TSL:1	n.643G>A		non_coding_transcript_exon	Exon 6 of 10	ENSP00000392464.1	Q5I0G3-3
	MDH1B	ENST00000454776.6	TSL:2	c.1282G>A	p.Val428Met	missense	Exon 8 of 12	ENSP00000389916.2	Q5I0G3-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.088
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.088
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.070	B
Vest4		0.25
MutPred		0.55		Loss of catalytic residue at V428 (P = 0.0057)
MVP		0.46
MPC		0.16
ClinPred		0.078	T
GERP RS		-0.30
Varity_R		0.036
gMVP		0.38
Mutation Taster		=96/4	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

hg19: chr2-207611085;