11-74493453-C-G

Variant names:

• chr11-74493453-C-G
• rs990796543
• NM_001144869.3:c.251G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001144869.3(LIPT2):​c.251G>C​(p.Gly84Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

Genes affected

LIPT2 (HGNC:37216): (lipoyl(octanoyl) transferase 2) This gene encodes a mitochondrial protein that catalyzes the transfer of octanoic acid to lipoate-dependent enzymes such as octanoyl-ACP. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

LIPT2-AS1 (HGNC:56172): (LIPT2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38356978).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPT2	NM_001144869.3	c.251G>C	p.Gly84Ala	missense_variant	Exon 1 of 2	ENST00000310109.5	NP_001138341.1
LIPT2	NM_001329941.2	c.251G>C	p.Gly84Ala	missense_variant	Exon 1 of 2		NP_001316870.1
LIPT2	NM_001329942.2	c.237+14G>C		intron_variant	Intron 1 of 1		NP_001316871.1
LIPT2-AS1	NR_171028.1	n.74C>G		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPT2	ENST00000310109.5	c.251G>C	p.Gly84Ala	missense_variant	Exon 1 of 2	2	NM_001144869.3	ENSP00000309463.4
LIPT2-AS1	ENST00000526036.1	n.88C>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
LIPT2	ENST00000528085.1	c.180+14G>C		intron_variant	Intron 1 of 1	3		ENSP00000433005.1
LIPT2	ENST00000527115.1	c.-140G>C		upstream_gene_variant		2		ENSP00000431210.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1339750 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 660250

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 1715038). This variant has not been reported in the literature in individuals affected with LIPT2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 84 of the LIPT2 protein (p.Gly84Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.42
Sift	Benign	0.034	D
Sift4G	Uncertain	0.031	D
Polyphen		0.15	B
Vest4		0.21
MutPred		0.45		Loss of catalytic residue at G84 (P = 0.0191);
MVP		0.18
ClinPred		0.86	D
GERP RS		3.6
Varity_R		0.24
gMVP		0.53

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: rs990796543; hg19: chr11-74204498;