16-2966377-C-A

Variant names:

• chr16-2966377-C-A
• rs1006320008
• NM_172229.3:c.414C>A

Variant summary

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

The NM_172229.3(KREMEN2):​c.414C>A​(p.Ser138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000931 in 1,611,380 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S138I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: KREMEN2 NM_172229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.404

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.414C>A	p.Ser138Arg	missense_variant	Exon 4 of 9	ENST00000303746.10	NP_757384.1
KREMEN2	NM_001253726.2	c.414C>A	p.Ser138Arg	missense_variant	Exon 4 of 9		NP_001240655.1
KREMEN2	NM_024507.4	c.414C>A	p.Ser138Arg	missense_variant	Exon 4 of 8		NP_078783.1
KREMEN2	NM_001253725.2	c.414C>A	p.Ser138Arg	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.414C>A	p.Ser138Arg	missense_variant	Exon 4 of 9	1	NM_172229.3	ENSP00000304422.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

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

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1459210 Hom.: 0 Cov.: 33 AF XY: 0.00000827 AC XY: 6 AN XY: 725892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

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: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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.414C>A (p.S138R) alteration is located in exon 4 (coding exon 4) of the KREMEN2 gene. This alteration results from a C to A substitution at nucleotide position 414, causing the serine (S) at amino acid position 138 to be replaced by an arginine (R). 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	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L;L;L;L;L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D;.;.;.;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.017	D;.;.;.;T;.
Sift4G	Uncertain	0.0030	D;D;T;D;D;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.60
MutPred		0.43		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		0.78
MPC		2.4
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.24
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1006320008; hg19: chr16-3016378;