Variant 11-107330003-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152434.3(CWF19L2):c.2456C>T(p.Pro819Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000952 in 1,575,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

CWF19L2
NM_152434.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

CWF19L2 (HGNC:26508): (CWF19 like cell cycle control factor 2) Predicted to be involved in mRNA splicing, via spliceosome. Predicted to be part of post-mRNA release spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

CWF19L2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CWF19L2	NM_152434.3 linkuse as main transcript	c.2456C>T	p.Pro819Leu	missense_variant	17/18	ENST00000282251.10	NP_689647.2	Q2TBE0-1
CWF19L2	XM_047426419.1 linkuse as main transcript	c.1028C>T	p.Pro343Leu	missense_variant	10/11		XP_047282375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CWF19L2	ENST00000282251.10 linkuse as main transcript	c.2456C>T	p.Pro819Leu	missense_variant	17/18	1	NM_152434.3	ENSP00000282251.5		Q2TBE0-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000492

AC:

AN:

1423460

Hom.:

Cov.:

AF XY:

0.00000709

AC XY:

AN XY:

704956

show subpopulations

Gnomad4 AFR exome

AF:

0.000216

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.2456C>T (p.P819L) alteration is located in exon 17 (coding exon 17) of the CWF19L2 gene. This alteration results from a C to T substitution at nucleotide position 2456, causing the proline (P) at amino acid position 819 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

-0.18

MutationAssessor

Pathogenic

3.6

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-8.5

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.99

MutPred

0.79

Loss of disorder (P = 0.0728);

MVP

0.69

MPC

0.12

ClinPred

1.0

GERP RS

5.5

Varity_R

0.97

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over