Genetic Variant NM_172229.3:c.784C>G (chr16-2967053-C-G) – 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_172229.3(KREMEN2):c.784C>G(p.Leu262Val) 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 benign outcome for this variant. 13/22 in silico tools predict a benign 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. L262F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KREMEN2
NM_172229.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.79

Publications

1 publications found

Variant links:

Genes affected

KREMEN2 (HGNC:18797): (kringle containing transmembrane protein 2) This gene encodes a high-affinity dickkopf homolog 1 (DKK1) transmembrane receptor. A similar protein in mouse functions interacts with with DKK1 to block wingless (WNT)/beta-catenin signaling. The encoded protein forms a ternary membrane complex with DKK1 and the WNT receptor lipoprotein receptor-related protein 6 (LRP6), and induces rapid endocytosis and removal of LRP6 from the plasma membrane. It contains extracellular kringle, WSC, and CUB domains. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

KREMEN2 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=0.2184909).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172229.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KREMEN2	NM_172229.3	MANE Select	c.784C>G	p.Leu262Val	missense	Exon 6 of 9	NP_757384.1	Q8NCW0-1
KREMEN2	NM_001253726.2		c.667C>G	p.Leu223Val	missense	Exon 6 of 9	NP_001240655.1	Q8NCW0-5
KREMEN2	NM_024507.4		c.784C>G	p.Leu262Val	missense	Exon 6 of 8	NP_078783.1	Q8NCW0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KREMEN2	ENST00000303746.10	TSL:1 MANE Select	c.784C>G	p.Leu262Val	missense	Exon 6 of 9	ENSP00000304422.5	Q8NCW0-1
KREMEN2	ENST00000575769.1	TSL:1	c.784C>G	p.Leu262Val	missense	Exon 6 of 8	ENSP00000460917.1	Q8NCW0-2
KREMEN2	ENST00000319500.11	TSL:1	c.784C>G	p.Leu262Val	missense	Exon 6 of 8	ENSP00000322079.6	Q8NCW0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

127072

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1382548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682100

African (AFR)

AF:

0.00

AC:

AN:

29936

American (AMR)

AF:

0.00

AC:

AN:

35214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24748

East Asian (EAS)

AF:

0.00

AC:

AN:

34512

South Asian (SAS)

AF:

0.00

AC:

AN:

78438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075612

Other (OTH)

AF:

0.00

AC:

AN:

57526

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000150

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.034

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.57

PhyloP100

1.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.4

REVEL

Benign

0.031

Sift

Benign

0.042

Sift4G

Uncertain

0.021

Polyphen

0.11

Vest4

0.20

MutPred

0.47

Loss of disorder (P = 0.0755)

MVP

0.30

MPC

1.5

ClinPred

0.43

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.59

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over