20-45648739-C-T

Variant names:

• chr20-45648739-C-T
• NM_147197.2:c.244G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_147197.2(WFDC11):​c.244G>A​(p.Glu82Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WFDC11 NM_147197.2 missense, splice_region
• Scores: Splicing: ADA: 0.0002835
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.977
• Publications: 0 publications found

Genes affected

WFDC11 (HGNC:20478): (WAP four-disulfide core domain 11) This gene encodes a member of the WAP-type four-disulfide core (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. Most WFDC gene members are localized to chromosome 20q12-q13 in two clusters: centromeric and telomeric. This gene belongs to the telomeric cluster. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070429176).
• BP6: Variant 20-45648739-C-T is Benign according to our data. Variant chr20-45648739-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3816326.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_147197.2. 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
	WFDC11	NM_147197.2	MANE Select	c.244G>A	p.Glu82Lys	missense splice_region	Exon 5 of 5	NP_671730.1	Q8NEX6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WFDC11	ENST00000324384.4	TSL:1 MANE Select	c.244G>A	p.Glu82Lys	missense splice_region	Exon 5 of 5	ENSP00000318753.3	Q8NEX6
	WFDC11	ENST00000356562.6	TSL:1	c.244G>A	p.Glu82Lys	missense splice_region	Exon 5 of 5	ENSP00000348968.2	Q8NEX6
	WFDC11	ENST00000618797.4	TSL:5	c.244G>A	p.Glu82Lys	missense splice_region	Exon 4 of 4	ENSP00000479579.1	Q8NEX6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.11
DANN	Benign	0.55
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00053	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.98
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.034
Sift	Benign	0.21	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.39		Gain of methylation at E82 (P = 0.0036)
MVP		0.014
MPC		0.011
ClinPred		0.15	T
GERP RS		-6.7
Varity_R		0.037
gMVP		0.28
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: 0

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

Other links and lift over

hg19: chr20-44277378; COSMIC: COSV100180799;