2-43935181-T-C

Variant names:

• chr2-43935181-T-C
• rs17424646
• NM_133259.4:c.2505-303A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_133259.4(LRPPRC):​c.2505-303A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 152,292 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.087 (650 hom., cov: 33)
• Consequence: LRPPRC NM_133259.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.358
• Publications: 3 publications found

Genes affected

LRPPRC (HGNC:15714): (leucine rich pentatricopeptide repeat containing) This gene encodes a leucine-rich protein that has multiple pentatricopeptide repeats (PPR). The precise role of this protein is unknown but studies suggest it may play a role in cytoskeletal organization, vesicular transport, or in transcriptional regulation of both nuclear and mitochondrial genes. The protein localizes primarily to mitochondria and is predicted to have an N-terminal mitochondrial targeting sequence. Mutations in this gene are associated with the French-Canadian type of Leigh syndrome. [provided by RefSeq, Mar 2012]

LRPPRC Gene-Disease associations (from GenCC):

• congenital lactic acidosis, Saguenay-Lac-Saint-Jean type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• cytochrome-c oxidase deficiency disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-43935181-T-C is Benign according to our data. Variant chr2-43935181-T-C is described in ClinVar as Benign. ClinVar VariationId is 684318.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRPPRC	NM_133259.4	c.2505-303A>G		intron_variant	Intron 23 of 37	ENST00000260665.12	NP_573566.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRPPRC	ENST00000260665.12	c.2505-303A>G		intron_variant	Intron 23 of 37	1	NM_133259.4	ENSP00000260665.7

Frequencies

GnomAD3 genomes AF: 0.0872 AC: 13264 AN: 152174 Hom.: 652 Cov.: 33

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0548

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0802

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

GnomAD4 genome AF: 0.0870 AC: 13253 AN: 152292 Hom.: 650 Cov.: 33 AF XY: 0.0864 AC XY: 6437 AN XY: 74474

African (AFR) AF: 0.0782 AC: 3250 AN: 41562

American (AMR) AF: 0.0547 AC: 838 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.143 AC: 688 AN: 4826

European-Finnish (FIN) AF: 0.0693 AC: 735 AN: 10612

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6958 AN: 68002

Other (OTH) AF: 0.0794 AC: 168 AN: 2116

Alfa AF: 0.101 Hom.: 1141

Bravo AF: 0.0825

Asia WGS AF: 0.0530 AC: 183 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.5
DANN	Benign	0.53
PhyloP100		0.36
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: rs17424646; hg19: chr2-44162320;