chr9-136412321-C-T

Variant names:

• chr9-136412321-C-T
• rs73566911
• NM_015160.3:c.274+122C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015160.3(PMPCA):​c.274+122C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 852,944 control chromosomes in the GnomAD database, including 2,672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1539 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1133 hom.)
• Consequence: PMPCA NM_015160.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.33
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 9-136412321-C-T is Benign according to our data. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-136412321-C-T is described in CliVar as Benign. Clinvar id is 1293196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMPCA	NM_015160.3	c.274+122C>T		intron_variant	Intron 2 of 12	ENST00000371717.8	NP_055975.1
PMPCA	NM_001282946.2	c.-25+122C>T		intron_variant	Intron 2 of 12		NP_001269875.1
PMPCA	NM_001282944.2	c.-25+122C>T		intron_variant	Intron 2 of 11		NP_001269873.1
PMPCA	XM_005266059.4	c.274+122C>T		intron_variant	Intron 2 of 11		XP_005266116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMPCA	ENST00000371717.8	c.274+122C>T		intron_variant	Intron 2 of 12	1	NM_015160.3	ENSP00000360782.3

Frequencies

GnomAD3 genomes AF: 0.0938 AC: 14258 AN: 152052 Hom.: 1530 Cov.: 33

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00933

Gnomad FIN AF: 0.00359

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.104

GnomAD4 exome AF: 0.0341 AC: 23917 AN: 700774 Hom.: 1133 Cov.: 9 AF XY: 0.0322 AC XY: 11920 AN XY: 370216

African (AFR) AF: 0.266 AC: 4969 AN: 18672

American (AMR) AF: 0.0418 AC: 1683 AN: 40286

Ashkenazi Jewish (ASJ) AF: 0.0967 AC: 1814 AN: 18764

East Asian (EAS) AF: 0.0000833 AC: 3 AN: 36004

South Asian (SAS) AF: 0.00999 AC: 637 AN: 63790

European-Finnish (FIN) AF: 0.00560 AC: 275 AN: 49118

Middle Eastern (MID) AF: 0.103 AC: 411 AN: 4002

European-Non Finnish (NFE) AF: 0.0281 AC: 12243 AN: 435202

Other (OTH) AF: 0.0539 AC: 1882 AN: 34936

GnomAD4 genome AF: 0.0939 AC: 14293 AN: 152170 Hom.: 1539 Cov.: 33 AF XY: 0.0908 AC XY: 6758 AN XY: 74408

African (AFR) AF: 0.256 AC: 10625 AN: 41480

American (AMR) AF: 0.0699 AC: 1068 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00934 AC: 45 AN: 4818

European-Finnish (FIN) AF: 0.00359 AC: 38 AN: 10592

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0278 AC: 1893 AN: 68018

Other (OTH) AF: 0.103 AC: 217 AN: 2112

Alfa AF: 0.0273 Hom.: 43

Bravo AF: 0.107

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.17
DANN	Benign	0.39
PhyloP100		-3.3
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: rs73566911; hg19: chr9-139306773;