Genetic Variant NM_016041.5:c.44C>T (chr17-5486118-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_016041.5(DERL2):c.44C>T(p.Pro15Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DERL2
NM_016041.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.57

Publications

0 publications found

Variant links:

Genes affected

DERL2 (HGNC:17943): (derlin 2) Proteins that are unfolded or misfolded in the endoplasmic reticulum (ER) must be refolded or degraded to maintain the homeostasis of the ER. DERL2 is involved in the degradation of misfolded glycoproteins in the ER (Oda et al., 2006 [PubMed 16449189]).[supplied by OMIM, Mar 2008]

DERL2 links:

MIS12 (HGNC:24967): (MIS12 kinetochore complex component) Involved in attachment of mitotic spindle microtubules to kinetochore and kinetochore assembly. Located in kinetochore and nucleus. Part of MIS12/MIND type complex. [provided by Alliance of Genome Resources, Apr 2022]

MIS12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016041.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DERL2	NM_016041.5	MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 1 of 7	NP_057125.2
DERL2	NM_001304777.2		c.44C>T	p.Pro15Leu	missense	Exon 1 of 7	NP_001291706.1
DERL2	NM_001304779.2		c.44C>T	p.Pro15Leu	missense	Exon 1 of 4	NP_001291708.1	I3L3R8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DERL2	ENST00000158771.9	TSL:1 MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 1 of 7	ENSP00000158771.4	Q9GZP9
DERL2	ENST00000889580.1		c.44C>T	p.Pro15Leu	missense	Exon 1 of 8	ENSP00000559639.1
DERL2	ENST00000889592.1		c.44C>T	p.Pro15Leu	missense	Exon 1 of 8	ENSP00000559651.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247714

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000550

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459256

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33386

American (AMR)

AF:

0.00

AC:

AN:

44628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

86080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5308

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111120

Other (OTH)

AF:

0.00

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.97

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

5.6

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.25

Sift

Benign

0.17

Sift4G

Benign

0.67

Polyphen

0.0060

Vest4

0.32

MutPred

0.62

Loss of phosphorylation at Y10 (P = 0.0818)

MVP

0.64

MPC

0.75

ClinPred

0.49

GERP RS

6.1

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.16

gMVP

0.76

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over