12-21637150-A-G

Position:

• chr12-21637150-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002300.8(LDHB):​c.758T>C​(p.Ile253Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,451,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LDHB NM_002300.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.31

Genes affected

LDHB (HGNC:6541): (lactate dehydrogenase B) This gene encodes the B subunit of lactate dehydrogenase enzyme, which catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+ in a post-glycolysis process. Alternatively spliced transcript variants have been found for this gene. Recent studies have shown that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Mutations in this gene are associated with lactate dehydrogenase B deficiency. Pseudogenes have been identified on chromosomes X, 5 and 13. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDHB	NM_002300.8	c.758T>C	p.Ile253Thr	missense_variant	7/8	ENST00000350669.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDHB	ENST00000350669.5	c.758T>C	p.Ile253Thr	missense_variant	7/8	1	NM_002300.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250812 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135580

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451732 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 722894

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.024	B;B
Vest4		0.93
MutPred		0.62		Gain of catalytic residue at I253 (P = 0);Gain of catalytic residue at I253 (P = 0);
MVP		0.85
MPC		0.38
ClinPred		0.85	D
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.82
gMVP		0.93

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

Other links and lift over

dbSNP: rs774170965; hg19: chr12-21790084;