2-179945349-T-C

Variant names:

• chr2-179945349-T-C
• rs574337609
• NM_020943.3:c.2507A>G

Variant summary

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

The NM_020943.3(CWC22):​c.2507A>G​(p.His836Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,612,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. H836Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CWC22 NM_020943.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• 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=0.02365017).

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.2507A>G	p.His836Arg	missense	Exon 20 of 20	NP_065994.1	Q9HCG8
	CWC22	NM_001376029.1		c.2507A>G	p.His836Arg	missense	Exon 20 of 20	NP_001362958.1	Q9HCG8
	CWC22	NM_001376030.1		c.2507A>G	p.His836Arg	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.2507A>G	p.His836Arg	missense	Exon 20 of 20	ENSP00000387006.3	Q9HCG8
	CWC22	ENST00000918074.1		c.2507A>G	p.His836Arg	missense	Exon 20 of 20	ENSP00000588133.1
	CWC22	ENST00000910802.1		c.2501A>G	p.His834Arg	missense	Exon 20 of 20	ENSP00000580861.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000117 AC: 29 AN: 248076 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1460482 Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46 AN XY: 726526

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.0000449 AC: 2 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000651 AC: 56 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111508

Other (OTH) AF: 0.0000166 AC: 1 AN: 60288

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.060
Sift	Benign	0.030	D
Sift4G	Benign	0.71	T
Polyphen		0.012	B
Vest4		0.16
MutPred		0.16		Loss of ubiquitination at K841 (P = 0.0193)
MVP		0.20
MPC		0.13
ClinPred		0.051	T
GERP RS		4.0
Varity_R		0.063
gMVP		0.056
Mutation Taster		=94/6	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: rs574337609; hg19: chr2-180810076;