16-2964570-T-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_172229.3(KREMEN2):c.50T>G(p.Leu17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,608,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

KREMEN2
NM_172229.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.356

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KREMEN2	NM_172229.3 link	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 9	ENST00000303746.10	NP_757384.1	Q8NCW0-1Q53F67
KREMEN2	NM_001253726.2 link	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 9		NP_001240655.1	Q8NCW0-5Q53F67
KREMEN2	NM_024507.4 link	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 8		NP_078783.1	Q8NCW0-3Q53F67
KREMEN2	NM_001253725.2 link	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 8		NP_001240654.1	Q8NCW0-6Q53F67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KREMEN2	ENST00000303746.10 link	c.50T>G	p.Leu17Arg	missense_variant	Exon 1 of 9	1	NM_172229.3	ENSP00000304422.5		Q8NCW0-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000701

AC:

AN:

242504

Hom.:

AF XY:

0.0000758

AC XY:

AN XY:

131856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000590

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000923

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000467

AC:

AN:

1456394

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

724526

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000906

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000175

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.50T>G (p.L17R) alteration is located in exon 1 (coding exon 1) of the KREMEN2 gene. This alteration results from a T to G substitution at nucleotide position 50, causing the leucine (L) at amino acid position 17 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

0.074

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

T;.;.;.;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.59

T;T;T;T;T;T

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.64

D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L;L;L;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

N;.;.;.;N;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.015

D;.;.;.;D;.

Sift4G

Uncertain

0.0050

D;D;D;D;D;D

Polyphen

0.41

B;P;.;.;P;P

Vest4

0.74

MutPred

0.64

Gain of disorder (P = 0.033);Gain of disorder (P = 0.033);Gain of disorder (P = 0.033);Gain of disorder (P = 0.033);Gain of disorder (P = 0.033);Gain of disorder (P = 0.033);

MVP

0.80

MPC

0.046

ClinPred

0.040

GERP RS

0.76

Varity_R

0.36

gMVP

0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over