16-2966376-G-T

Variant names:

• chr16-2966376-G-T
• rs1857505440
• NM_172229.3:c.413G>T

Variant summary

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

The NM_172229.3(KREMEN2):​c.413G>T​(p.Ser138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S138R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KREMEN2 NM_172229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

Genes affected

KREMEN2 (HGNC:18797): (kringle containing transmembrane protein 2) This gene encodes a high-affinity dickkopf homolog 1 (DKK1) transmembrane receptor. A similar protein in mouse functions interacts with with DKK1 to block wingless (WNT)/beta-catenin signaling. The encoded protein forms a ternary membrane complex with DKK1 and the WNT receptor lipoprotein receptor-related protein 6 (LRP6), and induces rapid endocytosis and removal of LRP6 from the plasma membrane. It contains extracellular kringle, WSC, and CUB domains. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

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 rank	MANE	Protein	UniProt
KREMEN2	NM_172229.3	c.413G>T	p.Ser138Ile	missense_variant	Exon 4 of 9	ENST00000303746.10	NP_757384.1
KREMEN2	NM_001253726.2	c.413G>T	p.Ser138Ile	missense_variant	Exon 4 of 9		NP_001240655.1
KREMEN2	NM_024507.4	c.413G>T	p.Ser138Ile	missense_variant	Exon 4 of 8		NP_078783.1
KREMEN2	NM_001253725.2	c.413G>T	p.Ser138Ile	missense_variant	Exon 4 of 8		NP_001240654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KREMEN2	ENST00000303746.10	c.413G>T	p.Ser138Ile	missense_variant	Exon 4 of 9	1	NM_172229.3	ENSP00000304422.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413G>T (p.S138I) alteration is located in exon 4 (coding exon 4) of the KREMEN2 gene. This alteration results from a G to T substitution at nucleotide position 413, causing the serine (S) at amino acid position 138 to be replaced by an isoleucine (I). 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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.51	D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	2.0	M;M;M;M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	D;.;.;.;D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.020	D;.;.;.;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.57
MutPred		0.38		Loss of glycosylation at S138 (P = 0.0106);Loss of glycosylation at S138 (P = 0.0106);Loss of glycosylation at S138 (P = 0.0106);Loss of glycosylation at S138 (P = 0.0106);Loss of glycosylation at S138 (P = 0.0106);Loss of glycosylation at S138 (P = 0.0106);
MVP		0.87
MPC		2.4
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.41
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs1857505440; hg19: chr16-3016377;