Variant 22-29094326-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039570.3(KREMEN1):c.166C>A(p.Pro56Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13543615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KREMEN1	NM_001039570.3 linkuse as main transcript	c.166C>A	p.Pro56Thr	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.166C>A	p.Pro56Thr	missense_variant	2/9	1	NM_001039570.3	ENSP00000383189.4	Q96MU8-3
KREMEN1	ENST00000407188.5 linkuse as main transcript	c.160C>A	p.Pro54Thr	missense_variant	2/9	1		ENSP00000385431.1	Q96MU8-1
KREMEN1	ENST00000327813.9 linkuse as main transcript	c.166C>A	p.Pro56Thr	missense_variant	2/10	2		ENSP00000331242.5	Q96MU8-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000801

AC:

AN:

249548

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000579

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

Apr 22, 2022

The c.166C>A (p.P56T) 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 166, causing the proline (P) at amino acid position 56 to be replaced by a threonine (T). 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

0.24

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

.;.;T

Eigen

Benign

0.10

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.70

.;.;N

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0050

D;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.83

P;B;.

Vest4

0.56

MutPred

0.57

Loss of catalytic residue at P56 (P = 0.0444);Loss of catalytic residue at P56 (P = 0.0444);.;

MVP

0.69

MPC

0.20

ClinPred

0.22

GERP RS

3.9

Varity_R

0.56

gMVP

0.64

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