2-179950552-C-G

Variant names:

• chr2-179950552-C-G
• rs374462893
• NM_020943.3:c.2100G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020943.3(CWC22):​c.2100G>C​(p.Glu700Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,612,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E700G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: CWC22 NM_020943.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.433
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025859147).

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.2100G>C	p.Glu700Asp	missense	Exon 19 of 20	NP_065994.1	Q9HCG8
	CWC22	NM_001376029.1		c.2100G>C	p.Glu700Asp	missense	Exon 19 of 20	NP_001362958.1	Q9HCG8
	CWC22	NM_001376030.1		c.2100G>C	p.Glu700Asp	missense	Exon 19 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.2100G>C	p.Glu700Asp	missense	Exon 19 of 20	ENSP00000387006.3	Q9HCG8
	CWC22	ENST00000404136.2	TSL:1	c.2100G>C	p.Glu700Asp	missense	Exon 19 of 20	ENSP00000384159.2	B7WP74
	CWC22	ENST00000918074.1		c.2100G>C	p.Glu700Asp	missense	Exon 19 of 20	ENSP00000588133.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 247584 AF XY: 0.0000968

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000372 AC: 544 AN: 1460776 Hom.: 1 Cov.: 31 AF XY: 0.000340 AC XY: 247 AN XY: 726640

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000449 AC: 499 AN: 1111338

Other (OTH) AF: 0.000730 AC: 44 AN: 60312

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74314

African (AFR) AF: 0.0000724 AC: 3 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000531 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.000273

EpiControl AF: 0.000179

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	0.057
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.062
DANN	Benign	0.46
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.43
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.032
Sift	Benign	0.61	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.087
MutPred		0.10		Gain of glycosylation at S697 (P = 0.2159)
MVP		0.072
MPC		0.094
ClinPred		0.0072	T
GERP RS		-3.1
Varity_R		0.025
gMVP		0.071
Mutation Taster		=95/5	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: rs374462893; hg19: chr2-180815279;