dbSNP rs781702398: CWC27:p.Ser206* (chr5-64788968-C-A) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_005869.4(CWC27):c.617C>A(p.Ser206*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000141 in 1,421,962 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CWC27
NM_005869.4 stop_gained

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.07

Publications

2 publications found

Variant links:

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)

CWC27 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-64788968-C-A is Pathogenic according to our data. Variant chr5-64788968-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 426074.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CWC27	NM_005869.4	MANE Select	c.617C>A	p.Ser206*	stop_gained	Exon 7 of 14	NP_005860.2
CWC27	NM_001297644.1		c.617C>A	p.Ser206*	stop_gained	Exon 7 of 13	NP_001284573.1
CWC27	NM_001297645.2		c.617C>A	p.Ser206*	stop_gained	Exon 7 of 11	NP_001284574.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CWC27	ENST00000381070.8	TSL:1 MANE Select	c.617C>A	p.Ser206*	stop_gained	Exon 7 of 14	ENSP00000370460.2
CWC27	ENST00000508024.2	TSL:1	c.617C>A	p.Ser206*	stop_gained	Exon 7 of 11	ENSP00000426802.1
CWC27	ENST00000693660.1		c.518C>A	p.Ser173*	stop_gained	Exon 6 of 13	ENSP00000509052.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000432

AC:

AN:

231318

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000605

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1421962

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706714

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

40824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24990

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38308

South Asian (SAS)

AF:

0.00

AC:

AN:

78976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090622

Other (OTH)

AF:

0.00

AC:

AN:

58470

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Metaphyseal chondrodysplasia-retinitis pigmentosa syndrome

Pathogenic:1

May 11, 2017

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

PhyloP100

6.1

Vest4

0.40

GERP RS

5.0

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over