Genetic Variant DEDD2:p.Arg309His (chr19-42199493-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_133328.4(DEDD2):c.926G>A(p.Arg309His) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DEDD2
NM_133328.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.25

Variant links:

Genes affected

DEDD2 (HGNC:24450): (death effector domain containing 2) This gene encodes a nuclear-localized protein containing a death effector domain (DED). The encoded protein may regulate the trafficking of caspases and other proteins into the nucleus during death receptor-induced apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

DEDD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41403964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEDD2	NM_133328.4 link	c.926G>A	p.Arg309His	missense_variant	Exon 5 of 5	ENST00000596251.6	NP_579874.1	Q8WXF8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEDD2	ENST00000596251.6 link	c.926G>A	p.Arg309His	missense_variant	Exon 5 of 5	1	NM_133328.4	ENSP00000471512.1		Q8WXF8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247422

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134418

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460560

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726624

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.00000450

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

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.926G>A (p.R309H) alteration is located in exon 5 (coding exon 4) of the DEDD2 gene. This alteration results from a G to A substitution at nucleotide position 926, causing the arginine (R) at amino acid position 309 to be replaced by a histidine (H). 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

0.26

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

.;T;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Benign

0.0097

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.6

.;L;L

PrimateAI

Uncertain

0.68

REVEL

Benign

0.21

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.36

MutPred

0.28

.;Loss of helix (P = 0.0196);Loss of helix (P = 0.0196);

MVP

0.58

MPC

1.7

ClinPred

0.88

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over