16-2967040-G-C

Variant names:

• chr16-2967040-G-C
• rs751600199
• NM_172229.3:c.771G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_172229.3(KREMEN2):​c.771G>C​(p.Glu257Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: KREMEN2 NM_172229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.992
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32563692).

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.771G>C	p.Glu257Asp	missense	Exon 6 of 9	NP_757384.1	Q8NCW0-1
	KREMEN2	NM_001253726.2		c.654G>C	p.Glu218Asp	missense	Exon 6 of 9	NP_001240655.1	Q8NCW0-5
	KREMEN2	NM_024507.4		c.771G>C	p.Glu257Asp	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.771G>C	p.Glu257Asp	missense	Exon 6 of 9	ENSP00000304422.5	Q8NCW0-1
	KREMEN2	ENST00000575769.1	TSL:1	c.771G>C	p.Glu257Asp	missense	Exon 6 of 8	ENSP00000460917.1	Q8NCW0-2
	KREMEN2	ENST00000319500.11	TSL:1	c.771G>C	p.Glu257Asp	missense	Exon 6 of 8	ENSP00000322079.6	Q8NCW0-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.44
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.99
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.097
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.98	D
Vest4		0.33
MutPred		0.34		Loss of catalytic residue at E257 (P = 0.0222)
MVP		0.47
MPC		1.7
ClinPred		0.75	D
GERP RS		1.1
Varity_R		0.22
gMVP		0.76

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

Other links and lift over

dbSNP: rs751600199; hg19: chr16-3017041;