chr12-21637141-C-T

Variant names:

• chr12-21637141-C-T
• rs145355418
• NM_002300.8:c.767G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002300.8(LDHB):​c.767G>A​(p.Ser256Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000381 in 1,605,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: LDHB NM_002300.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.06
• Publications: 6 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07558188).
• BS2: High AC in GnomAd4 at 83 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.767G>A	p.Ser256Asn	missense	Exon 7 of 8	NP_002291.1	Q5U077
	LDHB	NM_001315537.2		c.767G>A	p.Ser256Asn	missense	Exon 7 of 8	NP_001302466.1	A0A5F9ZHM4
	LDHB	NM_001174097.3		c.767G>A	p.Ser256Asn	missense	Exon 7 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.767G>A	p.Ser256Asn	missense	Exon 7 of 8	ENSP00000229319.1	P07195
	LDHB	ENST00000470985.3	TSL:1	n.240G>A		non_coding_transcript_exon	Exon 2 of 3
	ENSG00000285854	ENST00000647960.1		n.767G>A		non_coding_transcript_exon	Exon 7 of 23	ENSP00000497202.1	A0A3B3IS95

Frequencies

GnomAD3 genomes AF: 0.000546 AC: 83 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000375 AC: 94 AN: 250874 AF XY: 0.000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000363 AC: 528 AN: 1453302 Hom.: 0 Cov.: 28 AF XY: 0.000358 AC XY: 259 AN XY: 723528

African (AFR) AF: 0.0000600 AC: 2 AN: 33316

American (AMR) AF: 0.000380 AC: 17 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00418 AC: 109 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.000326 AC: 360 AN: 1104874

Other (OTH) AF: 0.000633 AC: 38 AN: 60064

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74398

African (AFR) AF: 0.0000963 AC: 4 AN: 41546

American (AMR) AF: 0.00288 AC: 44 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67936

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000511 Hom.: 1

Bravo AF: 0.000438

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Glycogen storage disease due to lactate dehydrogenase H-subunit deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.076	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.048	D
Polyphen		0.071	B
Vest4		0.85
MVP		0.84
MPC		0.31
ClinPred		0.19	T
GERP RS		4.7
Varity_R		0.94
gMVP		0.96
Mutation Taster		=17/83	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: rs145355418; hg19: chr12-21790075;