12-21641990-C-A

Variant names:

• chr12-21641990-C-A
• rs200917173
• NM_002300.8:c.557G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002300.8(LDHB):​c.557G>T​(p.Cys186Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,412 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C186Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LDHB NM_002300.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.99
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 8 AD gene.

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.557G>T	p.Cys186Phe	missense	Exon 5 of 8	NP_002291.1	Q5U077
	LDHB	NM_001315537.2		c.557G>T	p.Cys186Phe	missense	Exon 5 of 8	NP_001302466.1	A0A5F9ZHM4
	LDHB	NM_001174097.3		c.557G>T	p.Cys186Phe	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.557G>T	p.Cys186Phe	missense	Exon 5 of 8	ENSP00000229319.1	P07195
	ENSG00000285854	ENST00000647960.1		n.557G>T		non_coding_transcript_exon	Exon 5 of 23	ENSP00000497202.1	A0A3B3IS95
	LDHB	ENST00000673047.2		c.557G>T	p.Cys186Phe	missense	Exon 5 of 8	ENSP00000500484.2	A0A5F9ZHM4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251224 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461412 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111726

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.92	L
PhyloP100		6.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Benign	0.22
Sift	Benign	0.10	T
Sift4G	Benign	0.079	T
Polyphen		0.083	B
Vest4		0.28
MutPred		0.55		Gain of catalytic residue at W189 (P = 0.0024)
MVP		0.72
MPC		1.2
ClinPred		0.77	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.78
Mutation Taster		=63/37	polymorphism

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: rs200917173; hg19: chr12-21794924; COSMIC: COSV63364252; COSMIC: COSV63364252;