16-2967053-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KREMEN2	NM_172229.3	c.784C>T	p.Leu262Phe	missense_variant	Exon 6 of 9	ENST00000303746.10	NP_757384.1
KREMEN2	NM_001253726.2	c.667C>T	p.Leu223Phe	missense_variant	Exon 6 of 9		NP_001240655.1
KREMEN2	NM_024507.4	c.784C>T	p.Leu262Phe	missense_variant	Exon 6 of 8		NP_078783.1
KREMEN2	NM_001253725.2	c.667C>T	p.Leu223Phe	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.784C>T	p.Leu262Phe	missense_variant	Exon 6 of 9	1	NM_172229.3	ENSP00000304422.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000315 AC: 4 AN: 127072 Hom.: 0 AF XY: 0.0000287 AC XY: 2 AN XY: 69692

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 SAS 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

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: 0.0000149

Gnomad4 OTH exome AF: 0.0000522

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.784C>T (p.L262F) 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 784, causing the leucine (L) at amino acid position 262 to be replaced by a phenylalanine (F). 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	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;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N;N;.;.;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.81	N;.;.;.;N;.
REVEL	Benign	0.063
Sift	Benign	0.18	T;.;.;.;T;.
Sift4G	Benign	0.16	T;T;T;T;T;T
Polyphen		0.99	D;D;.;.;D;D
Vest4		0.12
MutPred		0.42		Loss of stability (P = 0.0459);Loss of stability (P = 0.0459);.;.;Loss of stability (P = 0.0459);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs759517828; hg19: chr16-3017054;