Genetic Variant CWF19L2:p.Val741Leu (chr11-107336695-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_152434.3(CWF19L2):c.2221G>T(p.Val741Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,481,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000098 ( 1 hom. )

Consequence

CWF19L2
NM_152434.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.88

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CWF19L2	NM_152434.3 link	c.2221G>T	p.Val741Leu	missense_variant	Exon 15 of 18	ENST00000282251.10	NP_689647.2	Q2TBE0-1
CWF19L2	XM_047426419.1 link	c.793G>T	p.Val265Leu	missense_variant	Exon 8 of 11		XP_047282375.1
CWF19L2	XR_007062452.1 link	n.2307G>T		non_coding_transcript_exon_variant	Exon 16 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CWF19L2	ENST00000282251.10 link	c.2221G>T	p.Val741Leu	missense_variant	Exon 15 of 18	1	NM_152434.3	ENSP00000282251.5		Q2TBE0-1

Frequencies

GnomAD3 genomes

AF:

0.0000666

AC:

AN:

150258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000597

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:

0.000486

GnomAD2 exomes

AF:

0.00

AC:

AN:

141214

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000976

AC:

AN:

1331554

Hom.:

Cov.:

AF XY:

0.00000604

AC XY:

AN XY:

661814

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27948

American (AMR)

AF:

0.000366

AC:

AN:

24588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23174

East Asian (EAS)

AF:

0.00

AC:

AN:

36260

South Asian (SAS)

AF:

0.00

AC:

AN:

71916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4864

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1036606

Other (OTH)

AF:

0.0000724

AC:

AN:

55232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000665

AC:

AN:

150374

Hom.:

Cov.:

AF XY:

0.0000682

AC XY:

AN XY:

73336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40916

American (AMR)

AF:

0.000597

AC:

AN:

15088

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67722

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2221G>T (p.V741L) alteration is located in exon 15 (coding exon 15) of the CWF19L2 gene. This alteration results from a G to T substitution at nucleotide position 2221, causing the valine (V) at amino acid position 741 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

0.62

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.2

PhyloP100

7.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.9

REVEL

Benign

0.25

Sift

Benign

0.068

Sift4G

Uncertain

0.055

Polyphen

0.88

Vest4

0.77

MutPred

0.78

Gain of phosphorylation at S739 (P = 0.2076);

MVP

0.30

MPC

0.067

ClinPred

0.91

GERP RS

4.6

Varity_R

0.54

gMVP

0.81

Mutation Taster

=42/58

disease causing

(source)

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

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11-107336695-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over