chr22-29098945-C-G

Position:

• chr22-29098945-C-G

Variant summary

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

The NM_001039570.3(KREMEN1):​c.344C>G​(p.Ala115Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign 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: Not reported in ClinVar
• Conservation: PhyloP100: 5.42

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KREMEN1	NM_001039570.3	c.344C>G	p.Ala115Gly	missense_variant	3/9	ENST00000400335.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KREMEN1	ENST00000400335.9	c.344C>G	p.Ala115Gly	missense_variant	3/9	1	NM_001039570.3	P1
KREMEN1	ENST00000407188.5	c.338C>G	p.Ala113Gly	missense_variant	3/9	1
KREMEN1	ENST00000327813.9	c.344C>G	p.Ala115Gly	missense_variant	3/10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	.;.;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;D;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.96	.;.;L
MutationTaster	Benign	0.81	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.064	T;D;T
Sift4G	Benign	0.069	T;T;T
Polyphen		0.14	B;P;.
Vest4		0.41
MutPred		0.59		Gain of relative solvent accessibility (P = 0.1259);Gain of relative solvent accessibility (P = 0.1259);.;
MVP		0.68
MPC		0.23
ClinPred		0.70	D
GERP RS		5.2
Varity_R		0.25
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr22-29494933;