12-21642024-T-C

Position:

chr12-21642024-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP4_StrongBP6

The NM_002300.8(LDHB):c.523A>G(p.Met175Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,613,626 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M175L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

LDHB
NM_002300.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 8.00

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.010553241).

BP6

Variant 12-21642024-T-C is Benign according to our data. Variant chr12-21642024-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 882255.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDHB	NM_002300.8 linkuse as main transcript	c.523A>G	p.Met175Val	missense_variant	5/8	ENST00000350669.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
LDHB	ENST00000350669.5 linkuse as main transcript	c.523A>G	p.Met175Val	missense_variant	5/8	1	NM_002300.8	P1
LDHB	ENST00000673047.2 linkuse as main transcript	c.523A>G	p.Met175Val	missense_variant	5/8
LDHB	ENST00000396076.5 linkuse as main transcript	c.523A>G	p.Met175Val	missense_variant	5/8	5		P1
LDHB	ENST00000396075.5 linkuse as main transcript	c.523A>G	p.Met175Val	missense_variant	5/6	3

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

280

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00616

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000386

AC:

AN:

251352

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00542

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000151

AC:

220

AN:

1461536

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00556

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.00184

AC:

280

AN:

152090

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

132

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00614

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000310

Hom.:

Bravo

AF:

0.00212

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000511

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease due to lactate dehydrogenase H-subunit deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

LDHB-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;T;.

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.025

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

L;L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.24

Sift

Uncertain

0.019

D;D;D

Sift4G

Uncertain

0.049

D;D;.

Polyphen

0.0080

B;B;.

Vest4

0.88

MVP

0.71

MPC

0.30

ClinPred

0.036

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over