chr2-206749095-T-C

Variant names:

• chr2-206749095-T-C
• rs765672010
• NM_001039845.3:c.1141A>G

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.1141A>G​(p.Ile381Val) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MDH1B NM_001039845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• 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=0.19381437).

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.1141A>G	p.Ile381Val	missense	Exon 7 of 12	NP_001034934.1	Q5I0G3-1
	MDH1B	NM_001282940.2		c.1141A>G	p.Ile381Val	missense	Exon 7 of 12	NP_001269869.1	Q5I0G3-2
	MDH1B	NM_001330223.2		c.847A>G	p.Ile283Val	missense	Exon 6 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.1141A>G	p.Ile381Val	missense	Exon 7 of 12	ENSP00000363533.3	Q5I0G3-1
	MDH1B	ENST00000432911.5	TSL:1	n.502A>G		non_coding_transcript_exon	Exon 5 of 10	ENSP00000392464.1	Q5I0G3-3
	MDH1B	ENST00000454776.6	TSL:2	c.1141A>G	p.Ile381Val	missense	Exon 7 of 12	ENSP00000389916.2	Q5I0G3-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251286 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

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	0.088
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.079
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.50	P
Vest4		0.17
MutPred		0.42		Gain of ubiquitination at K386 (P = 0.115)
MVP		0.45
MPC		0.36
ClinPred		0.65	D
GERP RS		5.8
Varity_R		0.11
gMVP		0.59
Mutation Taster		=90/10	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: rs765672010; hg19: chr2-207613819;