NM_005869.4:c.71T>C

Variant names:

• chr5-64774719-T-C
• rs781194080
• NM_005869.4:c.71T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005869.4(CWC27):​c.71T>C​(p.Ile24Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,597,212 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CWC27 NM_005869.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33
• Publications: 1 publications found

Genes affected

CWC27 (HGNC:10664): (CWC27 spliceosome associated cyclophilin) Predicted to enable peptidyl-prolyl cis-trans isomerase activity. Predicted to be involved in protein peptidyl-prolyl isomerization. Located in nucleoplasm. Part of U2-type precatalytic spliceosome and catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

CWC27 Gene-Disease associations (from GenCC):

• metaphyseal chondrodysplasia-retinitis pigmentosa syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005869.4. 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
	CWC27	NM_005869.4	MANE Select	c.71T>C	p.Ile24Thr	missense	Exon 2 of 14	NP_005860.2	Q6UX04-1
	CWC27	NM_001297644.1		c.71T>C	p.Ile24Thr	missense	Exon 2 of 13	NP_001284573.1	Q6UX04
	CWC27	NM_001297645.2		c.71T>C	p.Ile24Thr	missense	Exon 2 of 11	NP_001284574.1	D6REK3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CWC27	ENST00000381070.8	TSL:1 MANE Select	c.71T>C	p.Ile24Thr	missense	Exon 2 of 14	ENSP00000370460.2	Q6UX04-1
	CWC27	ENST00000508024.2	TSL:1	c.71T>C	p.Ile24Thr	missense	Exon 2 of 11	ENSP00000426802.1	D6REK3
	CWC27	ENST00000607786.2	TSL:6	c.-230T>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	ENSP00000509647.1	A0A8I5KY88

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000173 AC: 4 AN: 231164 AF XY: 0.00000797

Gnomad AFR exome AF: 0.0000663

Gnomad AMR exome AF: 0.0000669

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1444992 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 8 AN XY: 718722

African (AFR) AF: 0.0000308 AC: 1 AN: 32488

American (AMR) AF: 0.0000716 AC: 3 AN: 41912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 38860

South Asian (SAS) AF: 0.00 AC: 0 AN: 83022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1105236

Other (OTH) AF: 0.0000168 AC: 1 AN: 59572

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.91		Loss of stability (P = 0.0305)
MVP		0.69
MPC		0.58
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.95
Mutation Taster		=19/81	disease causing

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: rs781194080; hg19: chr5-64070546;