16-2967050-C-T

Variant names:

• chr16-2967050-C-T
• NM_172229.3:c.781C>T

Variant summary

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

The NM_172229.3(KREMEN2):​c.781C>T​(p.Arg261Cys) 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 (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KREMEN2 NM_172229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.650

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.781C>T	p.Arg261Cys	missense_variant	Exon 6 of 9	ENST00000303746.10	NP_757384.1
KREMEN2	NM_001253726.2	c.664C>T	p.Arg222Cys	missense_variant	Exon 6 of 9		NP_001240655.1
KREMEN2	NM_024507.4	c.781C>T	p.Arg261Cys	missense_variant	Exon 6 of 8		NP_078783.1
KREMEN2	NM_001253725.2	c.664C>T	p.Arg222Cys	missense_variant	Exon 6 of 8		NP_001240654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KREMEN2	ENST00000303746.10	c.781C>T	p.Arg261Cys	missense_variant	Exon 6 of 9	1	NM_172229.3	ENSP00000304422.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1384788 Hom.: 0 Cov.: 62 AF XY: 0.00 AC XY: 0 AN XY: 683240

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.781C>T (p.R261C) alteration is located in exon 6 (coding exon 6) of the KREMEN2 gene. This alteration results from a C to T substitution at nucleotide position 781, causing the arginine (R) at amino acid position 261 to be replaced by a cysteine (C). 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	0.38
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;.;.;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	D;.;.;.;N;.
REVEL	Benign	0.20
Sift	Uncertain	0.020	D;.;.;.;T;.
Sift4G	Benign	0.074	T;T;D;T;D;T
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.44
MutPred		0.60		Gain of catalytic residue at L262 (P = 0.0125);Gain of catalytic residue at L262 (P = 0.0125);.;.;Gain of catalytic residue at L262 (P = 0.0125);Gain of catalytic residue at L262 (P = 0.0125);
MVP		0.49
MPC		1.6
ClinPred		0.97	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr16-3017051;