22-29098915-G-C

Position:

• chr22-29098915-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001039570.3(KREMEN1):​c.314G>C​(p.Gly105Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KREMEN1 NM_001039570.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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]

ACMG classification

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, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KREMEN1	NM_001039570.3	c.314G>C	p.Gly105Ala	missense_variant	3/9	ENST00000400335.9	NP_001034659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KREMEN1	ENST00000400335.9	c.314G>C	p.Gly105Ala	missense_variant	3/9	1	NM_001039570.3	ENSP00000383189	P1
KREMEN1	ENST00000407188.5	c.308G>C	p.Gly103Ala	missense_variant	3/9	1		ENSP00000385431
KREMEN1	ENST00000327813.9	c.314G>C	p.Gly105Ala	missense_variant	3/10	2		ENSP00000331242

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 105 of the KREMEN1 protein (p.Gly105Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KREMEN1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KREMEN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.3	.;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.016	D;D;D
Sift4G	Benign	0.068	T;T;T
Polyphen		0.99	D;D;.
Vest4		0.71
MutPred		0.46		Loss of ubiquitination at K109 (P = 0.0801);Loss of ubiquitination at K109 (P = 0.0801);.;
MVP		0.78
MPC		0.32
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.86
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29494903;