2-206755302-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001039845.3(MDH1B):​c.617G>A​(p.Arg206His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MDH1B
NM_001039845.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.883
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05356291).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MDH1BNM_001039845.3 linkuse as main transcriptc.617G>A p.Arg206His missense_variant 5/12 ENST00000374412.8 NP_001034934.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MDH1BENST00000374412.8 linkuse as main transcriptc.617G>A p.Arg206His missense_variant 5/121 NM_001039845.3 ENSP00000363533 P4Q5I0G3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251062
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135688
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.0000110
AC XY:
8
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
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:
0.0000144
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000329
Hom.:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 09, 2023The c.617G>A (p.R206H) alteration is located in exon 5 (coding exon 5) of the MDH1B gene. This alteration results from a G to A substitution at nucleotide position 617, causing the arginine (R) at amino acid position 206 to be replaced by a histidine (H). 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
0.058
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.70
CADD
Benign
0.040
DANN
Benign
0.58
DEOGEN2
Benign
0.034
T;.;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.031
N
LIST_S2
Benign
0.47
T;T;T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.054
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.75
N;.;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.20
T
PROVEAN
Benign
-1.1
N;N;N
REVEL
Benign
0.0080
Sift
Benign
0.60
T;T;T
Sift4G
Benign
0.57
T;T;T
Polyphen
0.017
B;.;B
Vest4
0.17
MutPred
0.30
Gain of catalytic residue at Q207 (P = 0.1671);.;Gain of catalytic residue at Q207 (P = 0.1671);
MVP
0.085
MPC
0.13
ClinPred
0.012
T
GERP RS
-6.2
Varity_R
0.023
gMVP
0.17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764741072; hg19: chr2-207620026; API