11-107336628-T-C

Variant names:

• chr11-107336628-T-C
• rs149794929
• NM_152434.3:c.2288A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_152434.3(CWF19L2):​c.2288A>G​(p.Gln763Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,604,756 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q763H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: CWF19L2 NM_152434.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011035085).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CWF19L2	NM_152434.3	c.2288A>G	p.Gln763Arg	missense_variant	Exon 15 of 18	ENST00000282251.10	NP_689647.2
CWF19L2	XM_047426419.1	c.860A>G	p.Gln287Arg	missense_variant	Exon 8 of 11		XP_047282375.1
CWF19L2	XR_007062452.1	n.2374A>G		splice_region_variant, 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	c.2288A>G	p.Gln763Arg	missense_variant	Exon 15 of 18	1	NM_152434.3	ENSP00000282251.5

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152080 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000586 AC: 143 AN: 243850 AF XY: 0.000737

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000272

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.00131 AC: 1902 AN: 1452558 Hom.: 4 Cov.: 28 AF XY: 0.00135 AC XY: 972 AN XY: 722626

African (AFR) AF: 0.000181 AC: 6 AN: 33156

American (AMR) AF: 0.000297 AC: 13 AN: 43778

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39452

South Asian (SAS) AF: 0.000567 AC: 48 AN: 84622

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53332

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5722

European-Non Finnish (NFE) AF: 0.00158 AC: 1748 AN: 1106484

Other (OTH) AF: 0.00115 AC: 69 AN: 60026

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152198 Hom.: 0 Cov.: 31 AF XY: 0.000712 AC XY: 53 AN XY: 74428

African (AFR) AF: 0.000217 AC: 9 AN: 41536

American (AMR) AF: 0.000523 AC: 8 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 67996

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000846 Hom.: 9

Bravo AF: 0.000805

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.000601 AC: 73

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2288A>G (p.Q763R) alteration is located in exon 15 (coding exon 15) of the CWF19L2 gene. This alteration results from a A to G substitution at nucleotide position 2288, causing the glutamine (Q) at amino acid position 763 to be replaced by an arginine (R). 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	Benign	0.081
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	16
DANN	Benign	0.18
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.86	N
PhyloP100		2.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.093
Sift	Benign	0.69	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.076
MPC		0.015
ClinPred		0.0066	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.69
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 0

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

Other links and lift over

dbSNP: rs149794929; hg19: chr11-107207354; COSMIC: COSV56507922;