chr21-29006460-C-T

Position:

• chr21-29006460-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016940.3(RWDD2B):​c.917G>A​(p.Cys306Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RWDD2B NM_016940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73

Genes affected

RWDD2B (HGNC:1302): (RWD domain containing 2B)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RWDD2B	NM_016940.3	c.917G>A	p.Cys306Tyr	missense_variant	5/5	ENST00000493196.2	NP_058636.1
RWDD2B	NM_001320724.2	c.830G>A	p.Cys277Tyr	missense_variant	6/6		NP_001307653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RWDD2B	ENST00000493196.2	c.917G>A	p.Cys306Tyr	missense_variant	5/5	1	NM_016940.3	ENSP00000418693.1
RWDD2B	ENST00000286777.6	n.924G>A		non_coding_transcript_exon_variant	4/4	2
RWDD2B	ENST00000472184.1	n.1086G>A		non_coding_transcript_exon_variant	4/4	3
RWDD2B	ENST00000486719.5	n.1088G>A		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461486 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727054

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2022

The c.917G>A (p.C306Y) alteration is located in exon 5 (coding exon 5) of the RWDD2B gene. This alteration results from a G to A substitution at nucleotide position 917, causing the cysteine (C) at amino acid position 306 to be replaced by a tyrosine (Y). 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.043	D
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.77		Gain of phosphorylation at C306 (P = 0.0982);
MVP		0.61
MPC		0.93
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.61
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-30378781;