19-42199739-C-A

Variant names:

• chr19-42199739-C-A
• rs1344111303
• NM_133328.4:c.680G>T

Variant summary

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

The NM_133328.4(DEDD2):​c.680G>T​(p.Arg227Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,034 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R227Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DEDD2 NM_133328.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.06
• Publications: 0 publications found

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]

ACMG classification

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_133328.4. 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
	DEDD2	NM_133328.4	MANE Select	c.680G>T	p.Arg227Leu	missense	Exon 5 of 5	NP_579874.1	Q8WXF8-1
	DEDD2	NM_001270614.2		c.680G>T	p.Arg227Leu	missense	Exon 5 of 5	NP_001257543.1	Q8WXF8-1
	DEDD2	NM_001270615.2		c.665G>T	p.Arg222Leu	missense	Exon 5 of 5	NP_001257544.1	Q8WXF8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEDD2	ENST00000596251.6	TSL:1 MANE Select	c.680G>T	p.Arg227Leu	missense	Exon 5 of 5	ENSP00000471512.1	Q8WXF8-1
	DEDD2	ENST00000336034.8	TSL:1	c.665G>T	p.Arg222Leu	missense	Exon 5 of 5	ENSP00000336972.4	Q8WXF8-2
	DEDD2	ENST00000595337.5	TSL:3	c.680G>T	p.Arg227Leu	missense	Exon 5 of 5	ENSP00000470082.1	Q8WXF8-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461034 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111628

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.1
PrimateAI	Pathogenic	0.81	D
REVEL	Benign	0.21
Sift4G	Uncertain	0.0060	D
Polyphen		0.79	P
Vest4		0.77
MutPred		0.44		Loss of MoRF binding (P = 0.024)
MVP		0.60
MPC		0.98
ClinPred		0.94	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.53
gMVP		0.84
Mutation Taster		=64/36	polymorphism

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: rs1344111303; hg19: chr19-42703891; COSMIC: COSV105196341; COSMIC: COSV105196341;