16-2967053-C-T

Variant names:

• chr16-2967053-C-T
• rs759517828
• NM_172229.3:c.784C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172229.3(KREMEN2):​c.784C>T​(p.Leu262Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,382,548 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: KREMEN2 NM_172229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2229589).

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.784C>T	p.Leu262Phe	missense	Exon 6 of 9	NP_757384.1	Q8NCW0-1
	KREMEN2	NM_001253726.2		c.667C>T	p.Leu223Phe	missense	Exon 6 of 9	NP_001240655.1	Q8NCW0-5
	KREMEN2	NM_024507.4		c.784C>T	p.Leu262Phe	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.784C>T	p.Leu262Phe	missense	Exon 6 of 9	ENSP00000304422.5	Q8NCW0-1
	KREMEN2	ENST00000575769.1	TSL:1	c.784C>T	p.Leu262Phe	missense	Exon 6 of 8	ENSP00000460917.1	Q8NCW0-2
	KREMEN2	ENST00000319500.11	TSL:1	c.784C>T	p.Leu262Phe	missense	Exon 6 of 8	ENSP00000322079.6	Q8NCW0-3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000315 AC: 4 AN: 127072 AF XY: 0.0000287

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000417

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000645

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 19 AN: 1382548 Hom.: 0 Cov.: 60 AF XY: 0.0000132 AC XY: 9 AN XY: 682100

African (AFR) AF: 0.00 AC: 0 AN: 29936

American (AMR) AF: 0.00 AC: 0 AN: 35214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24748

East Asian (EAS) AF: 0.00 AC: 0 AN: 34512

South Asian (SAS) AF: 0.00 AC: 0 AN: 78438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5238

European-Non Finnish (NFE) AF: 0.0000149 AC: 16 AN: 1075612

Other (OTH) AF: 0.0000522 AC: 3 AN: 57526

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	0.0072
Eigen_PC	Benign	-0.0068
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.063
Sift	Benign	0.18	T
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.12
MutPred		0.42		Loss of stability (P = 0.0459)
MVP		0.36
MPC		1.4
ClinPred		0.27	T
GERP RS		3.2
Varity_R		0.21
gMVP		0.61
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs759517828; hg19: chr16-3017054;