9-136412050-T-C

Variant names:

• chr9-136412050-T-C
• rs776304951
• NM_015160.3:c.125T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015160.3(PMPCA):​c.125T>C​(p.Ile42Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I42F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMPCA NM_015160.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.78
• Publications: 1 publications found

Genes affected

PMPCA (HGNC:18667): (peptidase, mitochondrial processing subunit alpha) The protein encoded by this gene is found in the mitochondrion, where it represents the alpha subunit of a proteolytic heterodimer. This heterodimer is responsible for cleaving the transit peptide from nuclear-encoded mitochondrial proteins. Defects in this gene are a cause of spinocerebellar ataxia, autosomal recessive 2. [provided by RefSeq, Mar 2016]

PMPCA Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive spinocerebellar ataxia 2

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12628236).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015160.3. 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
	PMPCA	NM_015160.3	MANE Select	c.125T>C	p.Ile42Thr	missense	Exon 2 of 13	NP_055975.1	Q10713-1
	PMPCA	NM_001282946.2		c.-174T>C		5_prime_UTR	Exon 2 of 13	NP_001269875.1
	PMPCA	NM_001282944.2		c.-174T>C		5_prime_UTR	Exon 2 of 12	NP_001269873.1	Q10713-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMPCA	ENST00000371717.8	TSL:1 MANE Select	c.125T>C	p.Ile42Thr	missense	Exon 2 of 13	ENSP00000360782.3	Q10713-1
	PMPCA	ENST00000622209.4	TSL:1	n.134T>C		non_coding_transcript_exon	Exon 2 of 5
	PMPCA	ENST00000444897.3	TSL:2	c.125T>C	p.Ile42Thr	missense	Exon 2 of 12	ENSP00000408393.2	Q5SXN9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.019
Sift	Benign	0.065	T
Sift4G	Benign	0.11	T
Polyphen		0.030	B
Vest4		0.17
MutPred		0.33		Loss of stability (P = 0.0118)
MVP		0.26
MPC		0.19
ClinPred		0.42	T
GERP RS		3.3
Varity_R		0.087
gMVP		0.64
Mutation Taster		=79/21	polymorphism

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: rs776304951; hg19: chr9-139306502;