chr16-2967050-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172229.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KREMEN2	NM_172229.3	MANE Select	c.781C>T	p.Arg261Cys	missense	Exon 6 of 9	NP_757384.1	Q8NCW0-1
	KREMEN2	NM_001253726.2		c.664C>T	p.Arg222Cys	missense	Exon 6 of 9	NP_001240655.1	Q8NCW0-5
	KREMEN2	NM_024507.4		c.781C>T	p.Arg261Cys	missense	Exon 6 of 8	NP_078783.1	Q8NCW0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KREMEN2	ENST00000303746.10	TSL:1 MANE Select	c.781C>T	p.Arg261Cys	missense	Exon 6 of 9	ENSP00000304422.5	Q8NCW0-1
	KREMEN2	ENST00000575769.1	TSL:1	c.781C>T	p.Arg261Cys	missense	Exon 6 of 8	ENSP00000460917.1	Q8NCW0-2
	KREMEN2	ENST00000319500.11	TSL:1	c.781C>T	p.Arg261Cys	missense	Exon 6 of 8	ENSP00000322079.6	Q8NCW0-3

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

African (AFR) AF: 0.00 AC: 0 AN: 30216

American (AMR) AF: 0.00 AC: 0 AN: 35354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24812

East Asian (EAS) AF: 0.00 AC: 0 AN: 34718

South Asian (SAS) AF: 0.00 AC: 0 AN: 78600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076198

Other (OTH) AF: 0.00 AC: 0 AN: 57586

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.65
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.20
Sift	Uncertain	0.020	D
Sift4G	Benign	0.074	T
Polyphen		1.0	D
Vest4		0.44
MutPred		0.60		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

Other links and lift over

hg19: chr16-3017051;