2-240569071-C-T

Variant names:

• chr2-240569071-C-T
• rs374729262
• NM_018226.6:c.485C>T

Variant summary

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

The NM_018226.6(RNPEPL1):​c.485C>T​(p.Pro162Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000861 in 1,510,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P162S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: RNPEPL1 NM_018226.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.830
• Publications: 0 publications found

Genes affected

RNPEPL1 (HGNC:10079): (arginyl aminopeptidase like 1) Enables metalloaminopeptidase activity. Involved in proteolysis. [provided by Alliance of Genome Resources, Apr 2022]

ANKMY1 (HGNC:20987): (ankyrin repeat and MYND domain containing 1) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

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=0.19556963).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018226.6. 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
	RNPEPL1	NM_018226.6	MANE Select	c.485C>T	p.Pro162Leu	missense	Exon 1 of 11	NP_060696.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPEPL1	ENST00000270357.10	TSL:1 MANE Select	c.485C>T	p.Pro162Leu	missense	Exon 1 of 11	ENSP00000270357.4	Q9HAU8
	RNPEPL1	ENST00000971323.1		c.485C>T	p.Pro162Leu	missense	Exon 1 of 11	ENSP00000641382.1
	RNPEPL1	ENST00000971322.1		c.485C>T	p.Pro162Leu	missense	Exon 1 of 11	ENSP00000641381.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000568 AC: 6 AN: 105556 AF XY: 0.0000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000750

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000736 AC: 10 AN: 1357954 Hom.: 0 Cov.: 32 AF XY: 0.00000895 AC XY: 6 AN XY: 670236

African (AFR) AF: 0.00 AC: 0 AN: 27782

American (AMR) AF: 0.00 AC: 0 AN: 33660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24136

East Asian (EAS) AF: 0.000156 AC: 5 AN: 31954

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068878

Other (OTH) AF: 0.0000530 AC: 3 AN: 56588

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

Asia WGS AF: 0.000579 AC: 2 AN: 3470

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Benign	0.97
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.20	T
PhyloP100		0.83
PrimateAI	Pathogenic	0.88	D
GERP RS		2.1
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.17
gMVP		0.26
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs374729262; hg19: chr2-241508488;