Variant 11-74493391-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001144869.3(LIPT2):c.313C>G(p.Leu105Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,363,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L105R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

LIPT2
NM_001144869.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.961

Variant links:

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 links:

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

LIPT2-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-74493390-A-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPT2	NM_001144869.3 link	c.313C>G	p.Leu105Val	missense_variant	Exon 1 of 2	ENST00000310109.5	NP_001138341.1	A6NK58
LIPT2	NM_001329941.2 link	c.313C>G	p.Leu105Val	missense_variant	Exon 1 of 2		NP_001316870.1
LIPT2	NM_001329942.2 link	c.237+76C>G		intron_variant	Intron 1 of 1		NP_001316871.1
LIPT2-AS1	NR_171028.1 link	n.12G>C		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LIPT2	ENST00000310109.5 link	c.313C>G	p.Leu105Val	missense_variant	Exon 1 of 2	2	NM_001144869.3	ENSP00000309463.4	A6NK58
LIPT2-AS1	ENST00000526036.1 link	n.26G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
LIPT2	ENST00000528085.1 link	c.180+76C>G		intron_variant	Intron 1 of 1	3		ENSP00000433005.1	H0YD50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.33e-7

AC:

AN:

1363408

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672532

show subpopulations

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:

9.34e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: "Probably Damaging"; Align-GVGD: "Not Available"). 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. 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 leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 105 of the LIPT2 protein (p.Leu105Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.76

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

1.7

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

Sift4G

Benign

0.098

Polyphen

0.97

Vest4

0.42

MutPred

0.77

Gain of MoRF binding (P = 0.0781);

MVP

0.14

ClinPred

0.99

GERP RS

-3.3

Varity_R

0.73

gMVP

0.77

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over