22-29121475-G-T

Position:

chr22-29121475-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001039570.3(KREMEN1):c.471G>T(p.Arg157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,613,972 control chromosomes in the GnomAD database, including 2,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 156 hom., cov: 32)

Exomes 𝑓: 0.021 ( 1852 hom. )

Consequence

KREMEN1
NM_001039570.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.192

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019323826).

BP6

Variant 22-29121475-G-T is Benign according to our data. Variant chr22-29121475-G-T is described in ClinVar as [Benign]. Clinvar id is 1603774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KREMEN1	NM_001039570.3 linkuse as main transcript	c.471G>T	p.Arg157Ser	missense_variant	4/9	ENST00000400335.9	NP_001034659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KREMEN1	ENST00000400335.9 linkuse as main transcript	c.471G>T	p.Arg157Ser	missense_variant	4/9	1	NM_001039570.3	ENSP00000383189	P1	Q96MU8-3
KREMEN1	ENST00000407188.5 linkuse as main transcript	c.465G>T	p.Arg155Ser	missense_variant	4/9	1		ENSP00000385431		Q96MU8-1
KREMEN1	ENST00000327813.9 linkuse as main transcript	c.471G>T	p.Arg157Ser	missense_variant	4/10	2		ENSP00000331242		Q96MU8-2
KREMEN1	ENST00000453585.1 linkuse as main transcript	c.36G>T	p.Arg12Ser	missense_variant, NMD_transcript_variant	1/4	4		ENSP00000388228

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2497

AN:

152158

Hom.:

156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.188

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00650

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.0368

AC:

9187

AN:

249886

Hom.:

674

AF XY:

0.0436

AC XY:

5904

AN XY:

135488

show subpopulations

Gnomad AFR exome

AF:

0.00237

Gnomad AMR exome

AF:

0.00591

Gnomad ASJ exome

AF:

0.00725

Gnomad EAS exome

AF:

0.144

Gnomad SAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.0222

GnomAD4 exome

AF:

0.0206

AC:

30171

AN:

1461696

Hom.:

1852

Cov.:

AF XY:

0.0251

AC XY:

18249

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00197

Gnomad4 AMR exome

AF:

0.00610

Gnomad4 ASJ exome

AF:

0.00834

Gnomad4 EAS exome

AF:

0.138

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.00679

Gnomad4 OTH exome

AF:

0.0247

GnomAD4 genome

AF:

0.0163

AC:

2488

AN:

152276

Hom.:

156

Cov.:

AF XY:

0.0203

AC XY:

1510

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00219

Gnomad4 AMR

AF:

0.00550

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.148

Gnomad4 SAS

AF:

0.186

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.00650

Gnomad4 OTH

AF:

0.0118

Alfa

AF:

0.0112

Hom.:

103

Bravo

AF:

0.0118

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00229

AC:

ESP6500EA

AF:

0.00618

AC:

ExAC

AF:

0.0392

AC:

4753

Asia WGS

AF:

0.145

AC:

506

AN:

3478

EpiCase

AF:

0.00725

EpiControl

AF:

0.00593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.047

.;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.85

T;D;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.35

.;.;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.64

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.60

T;T;T

Sift4G

Benign

0.37

T;T;T

Polyphen

0.73

P;P;P

Vest4

0.55

MutPred

0.40

.;.;Loss of MoRF binding (P = 0.0686);

MPC

0.41

ClinPred

0.027

GERP RS

1.3

Varity_R

0.34

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

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