chr11-74492263-T-A

Position:

• chr11-74492263-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001144869.3(LIPT2):​c.568A>T​(p.Thr190Ser) variant causes a missense change. The variant allele was found at a frequency of 0.608 in 1,551,212 control chromosomes in the GnomAD database, including 289,463 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T190T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.55 (23913 hom., cov: 31)
  • Exomes 𝑓: 0.61 (265550 hom.)
• Consequence: LIPT2 NM_001144869.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.78

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3479864E-5).
• BP6: Variant 11-74492263-T-A is Benign according to our data. Variant chr11-74492263-T-A is described in ClinVar as [Benign]. Clinvar id is 1169390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPT2	NM_001144869.3	c.568A>T	p.Thr190Ser	missense_variant	2/2	ENST00000310109.5
LIPT2	NM_001329941.2	c.606A>T	p.Gly202=	synonymous_variant	2/2
LIPT2	NM_001329942.2	c.339A>T	p.Gly113=	synonymous_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPT2	ENST00000310109.5	c.568A>T	p.Thr190Ser	missense_variant	2/2	2	NM_001144869.3	P1
LIPT2	ENST00000527115.1	c.219A>T	p.Gly73=	synonymous_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.553 AC: 83885 AN: 151820 Hom.: 23924 Cov.: 31

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.552

GnomAD3 exomes AF: 0.580 AC: 90980 AN: 156780 Hom.: 26820 AF XY: 0.581 AC XY: 48249 AN XY: 83056

Gnomad AFR exome AF: 0.400

Gnomad AMR exome AF: 0.510

Gnomad ASJ exome AF: 0.634

Gnomad EAS exome AF: 0.661

Gnomad SAS exome AF: 0.508

Gnomad FIN exome AF: 0.599

Gnomad NFE exome AF: 0.631

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.614 AC: 858739 AN: 1399276 Hom.: 265550 Cov.: 49 AF XY: 0.612 AC XY: 422601 AN XY: 690142

Gnomad4 AFR exome AF: 0.397

Gnomad4 AMR exome AF: 0.516

Gnomad4 ASJ exome AF: 0.633

Gnomad4 EAS exome AF: 0.675

Gnomad4 SAS exome AF: 0.517

Gnomad4 FIN exome AF: 0.592

Gnomad4 NFE exome AF: 0.630

Gnomad4 OTH exome AF: 0.599

GnomAD4 genome AF: 0.552 AC: 83900 AN: 151936 Hom.: 23913 Cov.: 31 AF XY: 0.547 AC XY: 40604 AN XY: 74272

Gnomad4 AFR AF: 0.404

Gnomad4 AMR AF: 0.522

Gnomad4 ASJ AF: 0.635

Gnomad4 EAS AF: 0.649

Gnomad4 SAS AF: 0.517

Gnomad4 FIN AF: 0.600

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.549

Alfa AF: 0.621 Hom.: 22278

Bravo AF: 0.543

TwinsUK AF: 0.635 AC: 2354

ALSPAC AF: 0.639 AC: 2463

ExAC AF: 0.543 AC: 13690

Asia WGS AF: 0.526 AC: 1829 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

LIPT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.000033	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.98	P
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.27
Sift	Benign	0.080	T
Sift4G	Uncertain	0.022	D
Polyphen		0.077	B
Vest4		0.046
ClinPred		0.018	T
GERP RS		4.0
Varity_R		0.074
gMVP		0.51

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: rs586088; hg19: chr11-74203308; COSMIC: COSV59526495; COSMIC: COSV59526495;