15-63122055-G-C

Position:

• chr15-63122055-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032857.5(LACTB):​c.184G>C​(p.Gly62Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000392 in 1,276,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: LACTB NM_032857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

Genes affected

LACTB (HGNC:16468): (lactamase beta) This gene encodes a mitochondrially-localized protein that has sequence similarity to prokaryotic beta-lactamases. Many of the residues responsible for beta-lactamase activity are not conserved in this protein, suggesting it may have a different enzymatic function. Increased expression of the related mouse gene was found to be associated with obesity. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15614054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LACTB	NM_032857.5	c.184G>C	p.Gly62Arg	missense_variant	1/6	ENST00000261893.9	NP_116246.2
LACTB	NM_171846.4	c.184G>C	p.Gly62Arg	missense_variant	1/5		NP_741982.1
LACTB	NM_001288585.2	c.184G>C	p.Gly62Arg	missense_variant	1/5		NP_001275514.1
LACTB	XM_047432128.1	c.184G>C	p.Gly62Arg	missense_variant	1/6		XP_047288084.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LACTB	ENST00000261893.9	c.184G>C	p.Gly62Arg	missense_variant	1/6	1	NM_032857.5	ENSP00000261893.4
LACTB	ENST00000413507.3	c.184G>C	p.Gly62Arg	missense_variant	1/5	1		ENSP00000392956.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000392 AC: 5 AN: 1276394 Hom.: 0 Cov.: 34 AF XY: 0.00000480 AC XY: 3 AN XY: 625540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000143

Gnomad4 SAS exome AF: 0.0000156

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.184G>C (p.G62R) alteration is located in exon 1 (coding exon 1) of the LACTB gene. This alteration results from a G to C substitution at nucleotide position 184, causing the glycine (G) at amino acid position 62 to be replaced by an arginine (R). 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	Benign	0.24
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.10	T;D
Polyphen		0.36	B;.
Vest4		0.29
MutPred		0.30		Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);
MVP		0.43
MPC		0.43
ClinPred		0.34	T
GERP RS		1.9
Varity_R		0.18
gMVP		0.40

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

Other links and lift over

dbSNP: rs2036978475; hg19: chr15-63414254;