Genetic Variant NM_152434.3:c.2203A>G (chr11-107336713-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152434.3(CWF19L2):c.2203A>G(p.Met735Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,243,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

CWF19L2
NM_152434.3 missense, splice_region

Scores

Splicing: ADA: 0.0001939

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20542318).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152434.3. 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
	CWF19L2	NM_152434.3	MANE Select	c.2203A>G	p.Met735Val	missense splice_region	Exon 15 of 18	NP_689647.2	Q2TBE0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CWF19L2	ENST00000282251.10	TSL:1 MANE Select	c.2203A>G	p.Met735Val	missense splice_region	Exon 15 of 18	ENSP00000282251.5	Q2TBE0-1
CWF19L2	ENST00000431778.5	TSL:1	n.*51A>G		splice_region non_coding_transcript_exon	Exon 13 of 16	ENSP00000411736.1	H7C3G7
CWF19L2	ENST00000532251.1	TSL:1	n.*126A>G		splice_region non_coding_transcript_exon	Exon 12 of 15	ENSP00000434704.1	H0YE03

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000322

AC:

AN:

1243788

Hom.:

Cov.:

AF XY:

0.00000162

AC XY:

AN XY:

617626

show subpopulations

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

African (AFR)

AF:

0.0000394

AC:

AN:

25398

American (AMR)

AF:

0.000116

AC:

AN:

17262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21552

East Asian (EAS)

AF:

0.00

AC:

AN:

32750

South Asian (SAS)

AF:

0.00

AC:

AN:

65288

European-Finnish (FIN)

AF:

0.0000210

AC:

AN:

47634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3978

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

978252

Other (OTH)

AF:

0.00

AC:

AN:

51674

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0339446), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.0089

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.047

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

M_CAP

Benign

0.0052

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.88

PhyloP100

1.6

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

REVEL

Benign

0.10

Sift

Benign

0.60

Sift4G

Benign

0.38

Polyphen

0.0030

Vest4

0.35

MutPred

0.44

Gain of ubiquitination at K738 (P = 0.2122)

MVP

0.13

MPC

0.016

ClinPred

0.14

GERP RS

5.5

Varity_R

0.26

gMVP

0.60

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.018

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

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

Computational scores

Splicing

Publications

Other links and lift over