11-85636171-GT-TG

Variant names:

• chr11-85636171-GT-TG
• NM_018480.7:c.635_636delGTinsTG
• TMEM126B p.Gly212Val

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Very_Strong

The NM_018480.7(TMEM126B):​c.635_636delGTinsTG​(p.Gly212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM126B NM_018480.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• Publications: 0 publications found

Genes affected

TMEM126B (HGNC:30883): (transmembrane protein 126B) This gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. It interacts with NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 13. Naturally occurring mutations in this gene are associated with isolated complex I deficiency. A pseudogene of this gene has been defined on chromosome 9. [provided by RefSeq, Apr 2017]

TMEM126B Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 29

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_018480.7 (TMEM126B) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018480.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM126B	NM_018480.7	MANE Select	c.635_636delGTinsTG	p.Gly212Val	missense	N/A	NP_060950.3
	TMEM126B	NM_001193537.3		c.575_576delGTinsTG	p.Gly192Val	missense	N/A	NP_001180466.1
	TMEM126B	NM_001193538.3		c.545_546delGTinsTG	p.Gly182Val	missense	N/A	NP_001180467.1	Q8IUX1-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM126B	ENST00000358867.11	TSL:2 MANE Select	c.635_636delGTinsTG	p.Gly212Val	missense	N/A	ENSP00000351737.7	Q8IUX1-1
	TMEM126B	ENST00000393375.5	TSL:1	c.545_546delGTinsTG	p.Gly182Val	missense	N/A	ENSP00000377039.1	Q8IUX1-5
	TMEM126B	ENST00000529197.1	TSL:1	n.*684_*685delGTinsTG		non_coding_transcript_exon	Exon 6 of 6	ENSP00000436813.1	E9PKZ9

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-85347215;