Variant 22-29094301-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001039570.3(KREMEN1):c.141C>A(p.Asn47Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KREMEN1
NM_001039570.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.79

Variant links:

Genes affected

KREMEN1 (HGNC:17550): (kringle containing transmembrane protein 1) This gene encodes a high-affinity dickkopf homolog 1 (DKK1) transmembrane receptor that functionally cooperates with DKK1 to block wingless (WNT)/beta-catenin signaling. The encoded protein is a component of a membrane complex that modulates canonical WNT signaling through lipoprotein receptor-related protein 6 (LRP6). It contains extracellular kringle, WSC, and CUB domains. Mutations in this gene result in ectodermal dysplasia. This protein has also been found to be a functional receptor for Coxsackievirus A10 and may be an alternative entry receptor for SARS-CoV-2. [provided by RefSeq, Nov 2021]

KREMEN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KREMEN1	NM_001039570.3 linkuse as main transcript	c.141C>A	p.Asn47Lys	missense_variant	2/9	ENST00000400335.9	NP_001034659.2	Q96MU8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KREMEN1	ENST00000400335.9 linkuse as main transcript	c.141C>A	p.Asn47Lys	missense_variant	2/9	1	NM_001039570.3	ENSP00000383189.4	Q96MU8-3
KREMEN1	ENST00000407188.5 linkuse as main transcript	c.135C>A	p.Asn45Lys	missense_variant	2/9	1		ENSP00000385431.1	Q96MU8-1
KREMEN1	ENST00000327813.9 linkuse as main transcript	c.141C>A	p.Asn47Lys	missense_variant	2/10	2		ENSP00000331242.5	Q96MU8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249310

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135266

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2023

The c.141C>A (p.N47K) alteration is located in exon 2 (coding exon 2) of the KREMEN1 gene. This alteration results from a C to A substitution at nucleotide position 141, causing the asparagine (N) at amino acid position 47 to be replaced by a lysine (K). 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

Pathogenic

0.57

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

.;.;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.0

.;.;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.073

B;P;.

Vest4

0.72

MutPred

0.68

Gain of methylation at N47 (P = 0.015);Gain of methylation at N47 (P = 0.015);.;

MVP

0.70

MPC

0.32

ClinPred

0.98

GERP RS

4.0

Varity_R

0.80

gMVP

0.80

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