rs12517200

Variant names:

• chr5-140640336-A-G
• rs12517200
• NM_018502.5:c.198+485A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018502.5(TMCO6):​c.198+485A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 151,924 control chromosomes in the GnomAD database, including 5,916 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5916 hom., cov: 32)
• Consequence: TMCO6 NM_018502.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.267
• Publications: 16 publications found

Genes affected

TMCO6 (HGNC:28814): (transmembrane and coiled-coil domains 6) Predicted to enable nuclear import signal receptor activity. Predicted to be involved in protein import into nucleus. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

NDUFA2 (HGNC:7685): (NADH:ubiquinone oxidoreductase subunit A2) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

NDUFA2 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• cystic leukoencephalopathy without megalencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018502.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO6	NM_018502.5	MANE Select	c.198+485A>G		intron	N/A	NP_060972.3
	TMCO6	NM_001300980.2		c.198+485A>G		intron	N/A	NP_001287909.1
	TMCO6	NM_001300982.2		c.-234+485A>G		intron	N/A	NP_001287911.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO6	ENST00000394671.8	TSL:2 MANE Select	c.198+485A>G		intron	N/A	ENSP00000378166.3
	TMCO6	ENST00000252100.6	TSL:1	c.198+485A>G		intron	N/A	ENSP00000252100.6
	TMCO6	ENST00000513002.5	TSL:3	c.-130+485A>G		intron	N/A	ENSP00000421613.2

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41747 AN: 151826 Hom.: 5918 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.273

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.275 AC: 41771 AN: 151924 Hom.: 5916 Cov.: 32 AF XY: 0.278 AC XY: 20614 AN XY: 74222

African (AFR) AF: 0.258 AC: 10671 AN: 41422

American (AMR) AF: 0.292 AC: 4455 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3468

East Asian (EAS) AF: 0.166 AC: 860 AN: 5174

South Asian (SAS) AF: 0.216 AC: 1040 AN: 4808

European-Finnish (FIN) AF: 0.328 AC: 3452 AN: 10530

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.285 AC: 19393 AN: 67930

Other (OTH) AF: 0.273 AC: 574 AN: 2106

Alfa AF: 0.280 Hom.: 11528

Bravo AF: 0.270

Asia WGS AF: 0.212 AC: 736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.49
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12517200; hg19: chr5-140019921;