2-219384404-G-T

Variant names:

• chr2-219384404-G-T
• rs758123570
• NM_012100.4:c.814C>A

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.814C>A​(p.Arg272Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.000000685 in 1,459,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DNPEP NM_012100.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.814C>A	p.Arg272Arg	synonymous	Exon 9 of 15	NP_036232.2	Q9ULA0-1
	DNPEP	NM_001319116.2		c.838C>A	p.Arg280Arg	synonymous	Exon 9 of 15	NP_001306045.1	E7ETB3
	DNPEP	NM_001319118.2		c.772C>A	p.Arg258Arg	synonymous	Exon 9 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.814C>A	p.Arg272Arg	synonymous	Exon 9 of 15	ENSP00000273075.4	Q9ULA0-1
	DNPEP	ENST00000523282.6	TSL:2	c.838C>A	p.Arg280Arg	synonymous	Exon 9 of 15	ENSP00000431076.1	E7ETB3
	DNPEP	ENST00000851982.1		c.832C>A	p.Arg278Arg	synonymous	Exon 9 of 15	ENSP00000522041.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459546 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111002

Other (OTH) AF: 0.00 AC: 0 AN: 60306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.88
PhyloP100		6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.86		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758123570; hg19: chr2-220249126;