2-206751064-C-A

Variant names:

• chr2-206751064-C-A
• NM_001039845.3:c.922G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039845.3(MDH1B):​c.922G>T​(p.Val308Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,438,420 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MDH1B NM_001039845.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDH1B	NM_001039845.3	c.922G>T	p.Val308Leu	missense_variant	Exon 6 of 12	ENST00000374412.8	NP_001034934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDH1B	ENST00000374412.8	c.922G>T	p.Val308Leu	missense_variant	Exon 6 of 12	1	NM_001039845.3	ENSP00000363533.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1438420 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 715306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.922G>T (p.V308L) alteration is located in exon 6 (coding exon 6) of the MDH1B gene. This alteration results from a G to T substitution at nucleotide position 922, causing the valine (V) at amino acid position 308 to be replaced by a leucine (L). 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	Benign	0.32
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.53	D;D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.5	M;.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.25	B;.;B
Vest4		0.59
MutPred		0.46		Loss of MoRF binding (P = 0.1028);.;Loss of MoRF binding (P = 0.1028);
MVP		0.74
MPC		0.34
ClinPred		0.95	D
GERP RS		6.0
Varity_R		0.31
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: chr2-207615788; COSMIC: COSV65590474;