rs376062400

Variant names:

• chrM-12239-C-T
• rs376062400
• unassigned_transcript_4813:c.33C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The m.12239C>T variant in MT-TS2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant is seen in 3.631% of individuals in the GenBank dataset (BA1), including in haplogroup B4a (90.9% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 0.2% including in haplogroup B at 7%. If an affected individual is not a member this haplogroup, further evaluation of the variant in that particular individual should be considered. The computational predictor MitoTIP suggests this variant does not impact the function of this tRNA with a score in the 5th percentile, as does HmtVar with a score of <0.35 (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10581287/MONDO:0044970/014

• Frequency: Mitomap GenBank: 𝑓 0.033 (AC: 2042)
• Consequence: TRNS2 unassigned_transcript_4813 synonymous
• Scores: Mitotip Benign 2.8
• Clinical Significance: Benign reviewed by expert panel B:3 No linked disesase in Mitomap
• Conservation: PhyloP100: -9.03
• Publications: 1 publications found

Genes affected

TRNS2 (HGNC:7498): (mitochondrially encoded tRNA serine 2 (AGU/C))

MT-ND5 (HGNC:7461): (mitochondrially encoded NADH dehydrogenase 5) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND4 (HGNC:7459): (mitochondrially encoded NADH dehydrogenase 4) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Apr 2022]

TRNL2 (HGNC:7491): (mitochondrially encoded tRNA leucine 2 (CUN))

TRNH (HGNC:7487): (mitochondrially encoded tRNA histidine)

TRNH Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNS2	unassigned_transcript_4813	c.33C>T	p.Pro11Pro	synonymous_variant	Exon 1 of 1
ND5	unassigned_transcript_4815	c.-98C>T		upstream_gene_variant
TRNL2	unassigned_transcript_4814	c.-27C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND5	ENST00000361567.2	c.-98C>T		upstream_gene_variant		6		ENSP00000354813.2
MT-ND4	ENST00000361381.2	c.*102C>T		downstream_gene_variant		6		ENSP00000354961.2

Frequencies

Mitomap GenBank AF: 0.033 AC: 2042

Gnomad homoplasmic AF: 0.0022 AC: 123 AN: 56434

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56434

Alfa AF: 0.00 Hom.: 0

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Benign:1

Jan 10, 2022

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The m.12239C>T variant in MT-TS2 was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant is seen in 3.631% of individuals in the GenBank dataset (BA1), including in haplogroup B4a (90.9% of individuals). Furthermore, this variant is seen in the gnomAD dataset (v3.1.2) at an overall homoplasmic allele frequency of 0.2% including in haplogroup B at 7%. If an affected individual is not a member this haplogroup, further evaluation of the variant in that particular individual should be considered. The computational predictor MitoTIP suggests this variant does not impact the function of this tRNA with a score in the 5th percentile, as does HmtVar with a score of <0.35 (BP4). In summary, this variant meets criteria to be classified as benign. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: BA1, BP4. -

not provided Benign:1

Jun 02, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MELAS syndrome Benign:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.12239C>T variant in MT-TS2 gene is interpreted to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: BS1, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	2.8
Hmtvar	Benign	0.0
PhyloP100		-9.0

Other links and lift over

dbSNP: rs376062400; hg19: chrM-12240;