Genetic Variant DERL2:p.Thr109Ile (chr17-5481297-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016041.5(DERL2):c.326C>T(p.Thr109Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,344 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DERL2
NM_016041.5 missense, splice_region

Scores

Splicing: ADA: 0.03545

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.77

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DERL2	NM_016041.5 link	c.326C>T	p.Thr109Ile	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000158771.9	NP_057125.2	Q9GZP9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DERL2	ENST00000158771.9 link	c.326C>T	p.Thr109Ile	missense_variant, splice_region_variant	Exon 4 of 7	1	NM_016041.5	ENSP00000158771.4		Q9GZP9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458344

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725808

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.326C>T (p.T109I) alteration is located in exon 4 (coding exon 4) of the DERL2 gene. This alteration results from a C to T substitution at nucleotide position 326, causing the threonine (T) at amino acid position 109 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Benign

0.81

DEOGEN2

Benign

0.24

T;T;T;T

Eigen

Benign

0.00089

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

D;T;T;T

M_CAP

Benign

0.0089

MetaRNN

Uncertain

0.50

D;D;D;D

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.36

N;.;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.61

N;.;.;.

REVEL

Benign

0.23

Sift

Benign

0.59

T;.;.;.

Sift4G

Benign

0.54

T;T;T;T

Polyphen

0.0010

B;.;.;.

Vest4

0.84

MutPred

0.68

Gain of catalytic residue at L110 (P = 0.2852);.;Gain of catalytic residue at L110 (P = 0.2852);Gain of catalytic residue at L110 (P = 0.2852);

MVP

0.79

MPC

0.79

ClinPred

0.52

GERP RS

6.1

Varity_R

0.11

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.035

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over