NM_002300.8:c.973T>C

Variant names:

• chr12-21635574-A-G
• rs267607212
• NM_002300.8:c.973T>C

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.973T>C​(p.Trp325Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,262 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 Affects (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDHB NM_002300.8 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: 9.24
• Publications: 5 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, 0.926

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDHB	NM_002300.8	MANE Select	c.973T>C	p.Trp325Arg	missense	Exon 8 of 8	NP_002291.1
	LDHB	NM_001315537.2		c.973T>C	p.Trp325Arg	missense	Exon 8 of 8	NP_001302466.1
	LDHB	NM_001174097.3		c.973T>C	p.Trp325Arg	missense	Exon 8 of 8	NP_001167568.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDHB	ENST00000350669.5	TSL:1 MANE Select	c.973T>C	p.Trp325Arg	missense	Exon 8 of 8	ENSP00000229319.1
	LDHB	ENST00000470985.3	TSL:1	n.446T>C		non_coding_transcript_exon	Exon 3 of 3
	ENSG00000285854	ENST00000647960.1		n.837+1497T>C		intron	N/A	ENSP00000497202.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460262 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726476

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4522

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Affects

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Glycogen storage disease due to lactate dehydrogenase H-subunit deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.56	N
PhyloP100		9.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.010	D
Sift4G	Benign	0.44	T
Polyphen		0.33	B
Vest4		0.83
MutPred		0.77		Gain of disorder (P = 2e-04)
MVP		0.78
MPC		0.57
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.92
Mutation Taster		=0/100	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: rs267607212; hg19: chr12-21788508;