Genetic Variant NM_016027.3:c.686G>C (chr8-70640957-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_016027.3(LACTB2):c.686G>C(p.Arg229Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LACTB2
NM_016027.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0620

Publications

0 publications found

Variant links:

Genes affected

LACTB2 (HGNC:18512): (lactamase beta 2) Enables endoribonuclease activity; single-stranded RNA binding activity; and zinc ion binding activity. Involved in RNA phosphodiester bond hydrolysis, endonucleolytic. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

LACTB2 links:

LACTB2-AS1 (HGNC:27841): (LACTB2 antisense RNA 1)

LACTB2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2774195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LACTB2	NM_016027.3 link	c.686G>C	p.Arg229Pro	missense_variant	Exon 5 of 7	ENST00000276590.5	NP_057111.1	Q53H82A0A024R811
LACTB2-AS1	NR_038881.1 link	n.258-10856C>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LACTB2	ENST00000276590.5 link	c.686G>C	p.Arg229Pro	missense_variant	Exon 5 of 7	1	NM_016027.3	ENSP00000276590.4		Q53H82

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455612

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723840

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33196

American (AMR)

AF:

0.00

AC:

AN:

43542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39316

South Asian (SAS)

AF:

0.00

AC:

AN:

84408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109924

Other (OTH)

AF:

0.0000166

AC:

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 15, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.686G>C (p.R229P) alteration is located in exon 5 (coding exon 5) of the LACTB2 gene. This alteration results from a G to C substitution at nucleotide position 686, causing the arginine (R) at amino acid position 229 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.59

.;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L

PhyloP100

-0.062

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.092

Sift

Benign

0.18

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.45

P;P

Vest4

0.44

MutPred

0.55

Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);

MVP

0.17

MPC

0.033

ClinPred

0.44

GERP RS

-6.4

Varity_R

0.88

gMVP

0.78

Mutation Taster

=72/28

polymorphism

(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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NM_016027.3:c.686G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over