rs777713492

Variant summary

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

The NM_006103.4(WFDC2):​c.241C>A​(p.Pro81Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P81S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

WFDC2
NM_006103.4 missense

Scores

10
6
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.61
Variant links:
Genes affected
WFDC2 (HGNC:15939): (WAP four-disulfide core domain 2) This gene encodes a protein that is a member of the WFDC domain family. The WFDC domain, or WAP Signature motif, contains eight cysteines forming four disulfide bonds at the core of the protein, and functions as a protease inhibitor in many family members. This gene is expressed in pulmonary epithelial cells, and was also found to be expressed in some ovarian cancers. The encoded protein is a small secretory protein, which may be involved in sperm maturation. [provided by RefSeq, Jul 2008]

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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, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WFDC2NM_006103.4 linkc.241C>A p.Pro81Thr missense_variant Exon 3 of 4 ENST00000372676.8 NP_006094.3 Q14508-1A0A384MTN6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WFDC2ENST00000372676.8 linkc.241C>A p.Pro81Thr missense_variant Exon 3 of 4 1 NM_006103.4 ENSP00000361761.3 Q14508-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.69
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D;.;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.76
T;T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.2
H;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Pathogenic
-7.3
D;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0040
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.82
MutPred
0.88
Loss of methylation at K76 (P = 0.1399);.;.;
MVP
0.97
MPC
0.22
ClinPred
0.99
D
GERP RS
4.3
Varity_R
0.53
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-44108599; API