2-219374961-C-G

Variant names:

• chr2-219374961-C-G
• rs1459742930
• NM_012100.4:c.1301G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012100.4(DNPEP):​c.1301G>C​(p.Arg434Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R434Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNPEP NM_012100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80
• Publications: 0 publications found

Genes affected

DNPEP (HGNC:2981): (aspartyl aminopeptidase) The protein encoded by this gene is an aminopeptidase which prefers acidic amino acids, and specifically favors aspartic acid over glutamic acid. It is thought to be a cytosolic protein involved in general metabolism of intracellular proteins. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012100.4. 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
	DNPEP	NM_012100.4	MANE Select	c.1301G>C	p.Arg434Pro	missense	Exon 14 of 15	NP_036232.2	Q9ULA0-1
	DNPEP	NM_001319116.2		c.1325G>C	p.Arg442Pro	missense	Exon 14 of 15	NP_001306045.1	E7ETB3
	DNPEP	NM_001319118.2		c.1259G>C	p.Arg420Pro	missense	Exon 14 of 15	NP_001306047.1	E5RIA4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNPEP	ENST00000273075.9	TSL:1 MANE Select	c.1301G>C	p.Arg434Pro	missense	Exon 14 of 15	ENSP00000273075.4	Q9ULA0-1
	DNPEP	ENST00000523282.6	TSL:2	c.1325G>C	p.Arg442Pro	missense	Exon 14 of 15	ENSP00000431076.1	E7ETB3
	DNPEP	ENST00000851982.1		c.1319G>C	p.Arg440Pro	missense	Exon 14 of 15	ENSP00000522041.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.042	D
PhyloP100		3.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.75
Sift	Benign	0.098	T
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.91
MutPred		0.74		Loss of methylation at R442 (P = 0.0536)
MVP		0.76
MPC		0.81
ClinPred		0.96	D
GERP RS		5.3
gMVP		0.91
Mutation Taster		=26/74	disease causing

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: rs1459742930; hg19: chr2-220239683;