2-117817639-C-G

Position:

• chr2-117817639-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006773.4(DDX18):​c.281C>G​(p.Thr94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,613,352 control chromosomes in the GnomAD database, including 117,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (14675 hom., cov: 33)
  • Exomes 𝑓: 0.37 (102854 hom.)
• Consequence: DDX18 NM_006773.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.463

Genes affected

DDX18 (HGNC:2741): (DEAD-box helicase 18) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, and it is activated by Myc protein. [provided by RefSeq, Jul 2008]

DDX18 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5178924E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX18	NM_006773.4	c.281C>G	p.Thr94Ser	missense_variant	2/14	ENST00000263239.7	NP_006764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX18	ENST00000263239.7	c.281C>G	p.Thr94Ser	missense_variant	2/14	1	NM_006773.4	ENSP00000263239.2
DDX18	ENST00000474694.1	n.267C>G		non_coding_transcript_exon_variant	3/9	5

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64448 AN: 151878 Hom.: 14661 Cov.: 33

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.374 AC: 93733 AN: 250654 Hom.: 18541 AF XY: 0.380 AC XY: 51508 AN XY: 135712

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.329

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.200

Gnomad SAS exome AF: 0.460

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.371 AC: 541740 AN: 1461354 Hom.: 102854 Cov.: 36 AF XY: 0.374 AC XY: 271573 AN XY: 726988

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.380

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.464

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.366

Gnomad4 OTH exome AF: 0.372

GnomAD4 genome AF: 0.424 AC: 64512 AN: 151998 Hom.: 14675 Cov.: 33 AF XY: 0.424 AC XY: 31534 AN XY: 74288

Gnomad4 AFR AF: 0.582

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.463

Gnomad4 FIN AF: 0.359

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.376

Alfa AF: 0.336 Hom.: 2834

Bravo AF: 0.424

TwinsUK AF: 0.369 AC: 1368

ALSPAC AF: 0.363 AC: 1400

ESP6500AA AF: 0.579 AC: 2550

ESP6500EA AF: 0.365 AC: 3143

ExAC AF: 0.382 AC: 46379

Asia WGS AF: 0.351 AC: 1226 AN: 3478

EpiCase AF: 0.357

EpiControl AF: 0.367

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.2
DANN	Benign	0.92
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.12
Sift	Benign	0.26	T
Sift4G	Benign	0.76	T
Polyphen		0.020	B
Vest4		0.039
MutPred		0.042		Gain of phosphorylation at T94 (P = 0.0969);
MPC		0.15
ClinPred		0.0031	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.052

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

Other links and lift over

dbSNP: rs1052637; hg19: chr2-118575215; COSMIC: COSV54305397; COSMIC: COSV54305397;