chr8-70640987-A-G

Variant names:

• chr8-70640987-A-G
• rs368252116
• NM_016027.3:c.656T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016027.3(LACTB2):​c.656T>C​(p.Ile219Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,609,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: LACTB2 NM_016027.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.148
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058396727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LACTB2	NM_016027.3	c.656T>C	p.Ile219Thr	missense_variant	Exon 5 of 7	ENST00000276590.5	NP_057111.1
LACTB2-AS1	NR_038881.1	n.258-10826A>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LACTB2	ENST00000276590.5	c.656T>C	p.Ile219Thr	missense_variant	Exon 5 of 7	1	NM_016027.3	ENSP00000276590.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000324 AC: 8 AN: 246968 AF XY: 0.0000299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1457486 Hom.: 0 Cov.: 30 AF XY: 0.000149 AC XY: 108 AN XY: 724978

African (AFR) AF: 0.0000601 AC: 2 AN: 33274

American (AMR) AF: 0.00 AC: 0 AN: 43706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39328

South Asian (SAS) AF: 0.00 AC: 0 AN: 85134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000214 AC: 238 AN: 1110690

Other (OTH) AF: 0.000116 AC: 7 AN: 60184

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74490

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000642

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.656T>C (p.I219T) alteration is located in exon 5 (coding exon 5) of the LACTB2 gene. This alteration results from a T to C substitution at nucleotide position 656, causing the isoleucine (I) at amino acid position 219 to be replaced by a threonine (T). 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	0.088
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.049
DANN	Benign	0.57
DEOGEN2	Benign	0.092	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.63	N;N
PhyloP100		-0.15
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.61	N;N
REVEL	Benign	0.27
Sift	Benign	0.56	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0	B;B
Vest4		0.11
MVP		0.44
MPC		0.030
ClinPred		0.017	T
GERP RS		-5.6
Varity_R		0.081
gMVP		0.29
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs368252116; hg19: chr8-71553222;