Genetic Variant NM_018294.6:c.1262C>T (chr10-100236962-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018294.6(CWF19L1):c.1262C>T(p.Pro421Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,930 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: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CWF19L1
NM_018294.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.68

Publications

0 publications found

Variant links:

Genes affected

CWF19L1 (HGNC:25613): (CWF19 like cell cycle control factor 1) This gene encodes a member of the CWF19 protein family. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia-17 and mild cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

CWF19L1 links:

CHUK-DT (HGNC:55813): (CHUK divergent transcript)

CHUK-DT links:

SNORA12 (HGNC:32600): (small nucleolar RNA, H/ACA box 12) Small nucleolar RNAs (snoRNAs) are small noncoding RNAs involved in RNA processing. Box H/ACA snoRNAs, such as SNORA12, direct the conversion of uridine to pseudouridine at specific residues of ribosomal RNAs or small nuclear RNAs (snRNAs) (Gu et al., 2005).[supplied by OMIM, Mar 2008]

SNORA12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018294.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CWF19L1	NM_018294.6	MANE Select	c.1262C>T	p.Pro421Leu	missense	Exon 12 of 14	NP_060764.3
CWF19L1	NM_001303405.2		c.851C>T	p.Pro284Leu	missense	Exon 12 of 14	NP_001290334.1	Q69YN2-3
CWF19L1	NM_001303406.2		c.851C>T	p.Pro284Leu	missense	Exon 9 of 11	NP_001290335.1	Q69YN2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CWF19L1	ENST00000354105.10	TSL:1 MANE Select	c.1262C>T	p.Pro421Leu	missense	Exon 12 of 14	ENSP00000326411.6	Q69YN2-1
CWF19L1	ENST00000950162.1		c.1262C>T	p.Pro421Leu	missense	Exon 12 of 14	ENSP00000620221.1
CWF19L1	ENST00000950161.1		c.1259C>T	p.Pro420Leu	missense	Exon 12 of 14	ENSP00000620220.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1435930

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712536

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32406

American (AMR)

AF:

0.00

AC:

AN:

39636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24490

East Asian (EAS)

AF:

0.00

AC:

AN:

39450

South Asian (SAS)

AF:

0.00

AC:

AN:

82268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52778

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099978

Other (OTH)

AF:

0.0000169

AC:

AN:

59280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.36

MutationAssessor

Pathogenic

3.7

PhyloP100

7.7

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.93

MutPred

0.79

Gain of sheet (P = 0.0344)

MVP

0.77

MPC

0.63

ClinPred

0.99

GERP RS

5.3

Varity_R

0.77

gMVP

0.87

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over