16-2966183-A-G

Variant names:

• chr16-2966183-A-G
• rs766766667
• NM_172229.3:c.313A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172229.3(KREMEN2):​c.313A>G​(p.Thr105Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KREMEN2 NM_172229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

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=0.21491578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KREMEN2	NM_172229.3	c.313A>G	p.Thr105Ala	missense_variant	Exon 3 of 9	ENST00000303746.10	NP_757384.1
KREMEN2	NM_001253726.2	c.313A>G	p.Thr105Ala	missense_variant	Exon 3 of 9		NP_001240655.1
KREMEN2	NM_024507.4	c.313A>G	p.Thr105Ala	missense_variant	Exon 3 of 8		NP_078783.1
KREMEN2	NM_001253725.2	c.313A>G	p.Thr105Ala	missense_variant	Exon 3 of 8		NP_001240654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KREMEN2	ENST00000303746.10	c.313A>G	p.Thr105Ala	missense_variant	Exon 3 of 9	1	NM_172229.3	ENSP00000304422.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250950 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460426 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726542

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.313A>G (p.T105A) alteration is located in exon 3 (coding exon 3) of the KREMEN2 gene. This alteration results from a A to G substitution at nucleotide position 313, causing the threonine (T) at amino acid position 105 to be replaced by an alanine (A). 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	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;.;.;.;.;.
Eigen	Benign	-0.016
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.63	T;T;T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.7	L;L;L;L;L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N;.;.;.;N;.
REVEL	Benign	0.23
Sift	Benign	0.60	T;.;.;.;T;.
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.91	P;P;.;.;P;P
Vest4		0.43
MutPred		0.59		Loss of catalytic residue at T105 (P = 0.0385);Loss of catalytic residue at T105 (P = 0.0385);Loss of catalytic residue at T105 (P = 0.0385);Loss of catalytic residue at T105 (P = 0.0385);Loss of catalytic residue at T105 (P = 0.0385);Loss of catalytic residue at T105 (P = 0.0385);
MVP		0.78
MPC		1.4
ClinPred		0.42	T
GERP RS		2.8
Varity_R		0.085
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs766766667; hg19: chr16-3016184;