2-175181355-CAG-C

Variant names:

• chr2-175181355-CAG-C
• NM_001689.5:c.37_38delCT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001689.5(ATP5MC3):​c.37_38delCT​(p.Leu13AspfsTer23) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: ATP5MC3 NM_001689.5 frameshift, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.35
• Publications: 0 publications found

Genes affected

ATP5MC3 (HGNC:843): (ATP synthase membrane subunit c locus 3) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene is one of three genes that encode subunit c of the proton channel. Each of the three genes have distinct mitochondrial import sequences but encode the identical mature protein. Alternatively spliced transcript variants encoding different proteins have been identified. [provided by RefSeq, Jun 2010]

ATP5MC3 Gene-Disease associations (from GenCC):

• dystonia, early-onset, and/or spastic paraplegia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001689.5. 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
	ATP5MC3	NM_001689.5	MANE Select	c.37_38delCT	p.Leu13AspfsTer23	frameshift splice_region	Exon 2 of 5	NP_001680.1	P48201
	ATP5MC3	NM_001002258.5		c.37_38delCT	p.Leu13AspfsTer23	frameshift splice_region	Exon 1 of 4	NP_001002258.1	P48201
	ATP5MC3	NM_001190329.2		c.37_38delCT	p.Leu13AspfsTer23	frameshift splice_region	Exon 2 of 4	NP_001177258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5MC3	ENST00000284727.9	TSL:1 MANE Select	c.37_38delCT	p.Leu13AspfsTer23	frameshift splice_region	Exon 2 of 5	ENSP00000284727.4	P48201
	ATP5MC3	ENST00000392541.3	TSL:1	c.37_38delCT	p.Leu13AspfsTer23	frameshift splice_region	Exon 1 of 4	ENSP00000376324.3	P48201
	ATP5MC3	ENST00000941362.1		c.37_38delCT	p.Leu13AspfsTer23	frameshift splice_region	Exon 2 of 5	ENSP00000611421.1

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr2-176046083;