rs769392378

Variant names:

• chr5-1009547-C-T
• rs769392378
• NM_033120.4:c.128C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033120.4(NKD2):​c.128C>T​(p.Ala43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,339,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: NKD2 NM_033120.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0460
• Publications: 0 publications found

Genes affected

NKD2 (HGNC:17046): (NKD inhibitor of WNT signaling pathway 2) This gene encodes a member of a family of proteins that function as negative regulators of Wnt receptor signaling through interaction with Dishevelled family members. The encoded protein participates in the delivery of transforming growth factor alpha-containing vesicles to the cell membrane. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

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=0.07934043).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033120.4. 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
	NKD2	NM_033120.4	MANE Select	c.128C>T	p.Ala43Val	missense	Exon 3 of 10	NP_149111.1	Q969F2-1
	NKD2	NM_001271082.2		c.128C>T	p.Ala43Val	missense	Exon 3 of 11	NP_001258011.1	Q969F2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKD2	ENST00000296849.10	TSL:1 MANE Select	c.128C>T	p.Ala43Val	missense	Exon 3 of 10	ENSP00000296849.5	Q969F2-1
	NKD2	ENST00000274150.4	TSL:1	c.128C>T	p.Ala43Val	missense	Exon 3 of 11	ENSP00000274150.4	Q969F2-2
	NKD2	ENST00000866687.1		c.128C>T	p.Ala43Val	missense	Exon 4 of 11	ENSP00000536746.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000447 AC: 4 AN: 89390 AF XY: 0.0000197

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000228

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: 0.00000373 AC: 5 AN: 1339392 Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1 AN XY: 660724

African (AFR) AF: 0.00 AC: 0 AN: 27024

American (AMR) AF: 0.000170 AC: 5 AN: 29386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23622

East Asian (EAS) AF: 0.00 AC: 0 AN: 30252

South Asian (SAS) AF: 0.00 AC: 0 AN: 74504

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4178

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061616

Other (OTH) AF: 0.00 AC: 0 AN: 55666

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000625 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.084
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.046
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.079
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.84	P
Vest4		0.11
MutPred		0.18		Loss of loop (P = 0.0022)
MVP		0.43
MPC		0.042
ClinPred		0.10	T
GERP RS		1.4
Varity_R		0.051
gMVP		0.20
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs769392378; hg19: chr5-1009662;