12-21642032-C-A

Variant names:

• chr12-21642032-C-A
• rs118203895
• NM_002300.8:c.515G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002300.8(LDHB):​c.515G>T​(p.Arg172Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDHB NM_002300.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 0 publications found

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]

LDHB Gene-Disease associations (from GenCC):

• glycogen storage disease due to lactate dehydrogenase H-subunit deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285854 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002300.8. 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
	LDHB	NM_002300.8	MANE Select	c.515G>T	p.Arg172Leu	missense	Exon 5 of 8	NP_002291.1	Q5U077
	LDHB	NM_001315537.2		c.515G>T	p.Arg172Leu	missense	Exon 5 of 8	NP_001302466.1	A0A5F9ZHM4
	LDHB	NM_001174097.3		c.515G>T	p.Arg172Leu	missense	Exon 5 of 8	NP_001167568.1	Q5U077

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDHB	ENST00000350669.5	TSL:1 MANE Select	c.515G>T	p.Arg172Leu	missense	Exon 5 of 8	ENSP00000229319.1	P07195
	ENSG00000285854	ENST00000647960.1		n.515G>T		non_coding_transcript_exon	Exon 5 of 23	ENSP00000497202.1	A0A3B3IS95
	LDHB	ENST00000673047.2		c.515G>T	p.Arg172Leu	missense	Exon 5 of 8	ENSP00000500484.2	A0A5F9ZHM4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461382 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726980

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111640

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		5.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.94
MutPred		0.76		Gain of catalytic residue at S168 (P = 0)
MVP		0.93
MPC		0.37
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.86
Mutation Taster		=14/86	disease causing

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: rs118203895; hg19: chr12-21794966;