Genetic Variant LDHB:c.-6-658A>C (chr12-21655335-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002300.8(LDHB):c.-6-658A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.945 in 152,224 control chromosomes in the GnomAD database, including 68,472 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.94 ( 68472 hom., cov: 31)

Consequence

LDHB
NM_002300.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.312

Publications

2 publications found

Variant links:

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

LDHB links:

ENSG00000285854 (HGNC:):

ENSG00000285854 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDHB	NM_002300.8	MANE Select	c.-6-658A>C	intron	N/A	NP_002291.1	Q5U077
LDHB	NM_001315537.2		c.-6-658A>C	intron	N/A	NP_001302466.1	A0A5F9ZHM4
LDHB	NM_001174097.3		c.-6-658A>C	intron	N/A	NP_001167568.1	Q5U077

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LDHB	ENST00000350669.5	TSL:1 MANE Select	c.-6-658A>C	intron	N/A	ENSP00000229319.1	P07195
ENSG00000285854	ENST00000647960.1		n.-6-658A>C	intron	N/A	ENSP00000497202.1	A0A3B3IS95
LDHB	ENST00000895170.1		c.-664A>C	5_prime_UTR	Exon 1 of 7	ENSP00000565229.1

Frequencies

GnomAD3 genomes

AF:

0.945

AC:

143749

AN:

152106

Hom.:

68430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.814

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.979

Gnomad ASJ

AF:

0.968

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.992

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.954

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.945

AC:

143847

AN:

152224

Hom.:

68472

Cov.:

AF XY:

0.946

AC XY:

70405

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.814

AC:

33770

AN:

41482

American (AMR)

AF:

0.979

AC:

14963

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.968

AC:

3362

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5181

AN:

5182

South Asian (SAS)

AF:

0.993

AC:

4789

AN:

4824

European-Finnish (FIN)

AF:

1.00

AC:

10617

AN:

10618

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67949

AN:

68038

Other (OTH)

AF:

0.954

AC:

2014

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

354

709

1063

1418

1772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

910

1820

2730

3640

4550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.984

Hom.:

9683

Bravo

AF:

0.938

Asia WGS

AF:

0.981

AC:

3407

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.8

(source)

DANN

Benign

0.77

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over