NM_020943.3:c.2469A>T

Variant names:

• chr2-179945387-T-A
• rs1686265383
• NM_020943.3:c.2469A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020943.3(CWC22):​c.2469A>T​(p.Arg823Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CWC22 NM_020943.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0350
• Publications: 0 publications found

Genes affected

CWC22 (HGNC:29322): (CWC22 spliceosome associated protein homolog) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in cytosol and nuclear speck. Part of U2-type catalytic step 1 spliceosome; U2-type catalytic step 2 spliceosome; and U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083982766).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020943.3. 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
	CWC22	NM_020943.3	MANE Select	c.2469A>T	p.Arg823Ser	missense	Exon 20 of 20	NP_065994.1	Q9HCG8
	CWC22	NM_001376029.1		c.2469A>T	p.Arg823Ser	missense	Exon 20 of 20	NP_001362958.1	Q9HCG8
	CWC22	NM_001376030.1		c.2469A>T	p.Arg823Ser	missense	Exon 20 of 20	NP_001362959.1	Q9HCG8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWC22	ENST00000410053.8	TSL:1 MANE Select	c.2469A>T	p.Arg823Ser	missense	Exon 20 of 20	ENSP00000387006.3	Q9HCG8
	CWC22	ENST00000918074.1		c.2469A>T	p.Arg823Ser	missense	Exon 20 of 20	ENSP00000588133.1
	CWC22	ENST00000910802.1		c.2463A>T	p.Arg821Ser	missense	Exon 20 of 20	ENSP00000580861.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460670 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726630

African (AFR) AF: 0.0000599 AC: 2 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111422

Other (OTH) AF: 0.0000332 AC: 2 AN: 60326

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.035
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.034
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.12	T
Polyphen		0.31	B
Vest4		0.24
MutPred		0.24		Gain of phosphorylation at R823 (P = 0.005)
MVP		0.19
MPC		0.13
ClinPred		0.82	D
GERP RS		0.29
Varity_R		0.18
gMVP		0.21
Mutation Taster		=87/13	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: rs1686265383; hg19: chr2-180810114;