rs1011911801

Variant names:

• chr16-2966682-C-G
• NM_172229.3:c.527C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-2966682-C-G
• chr16-2966682-C-T

Variant summary

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

The NM_172229.3(KREMEN2):​c.527C>G​(p.Ser176Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,024 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S176F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KREMEN2 NM_172229.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27

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.527C>G	p.Ser176Cys	missense_variant	Exon 5 of 9	ENST00000303746.10	NP_757384.1
KREMEN2	NM_024507.4	c.527C>G	p.Ser176Cys	missense_variant	Exon 5 of 8		NP_078783.1
KREMEN2	NM_001253726.2	c.487-77C>G		intron_variant	Intron 4 of 8		NP_001240655.1
KREMEN2	NM_001253725.2	c.487-77C>G		intron_variant	Intron 4 of 7		NP_001240654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KREMEN2	ENST00000303746.10	c.527C>G	p.Ser176Cys	missense_variant	Exon 5 of 9	1	NM_172229.3	ENSP00000304422.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459024 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725882

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	2.0	M;M;M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D;.;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.010	D;.;D;.
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.56
MutPred		0.50		Loss of disorder (P = 0.0434);Loss of disorder (P = 0.0434);Loss of disorder (P = 0.0434);Loss of disorder (P = 0.0434);
MVP		0.88
MPC		2.1
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr16-3016683;