22-29073212-C-T

Position:

• chr22-29073212-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039570.3(KREMEN1):​c.82C>T​(p.Leu28Phe) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KREMEN1 NM_001039570.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.113

Genes affected

KREMEN1 (HGNC:17550): (kringle containing transmembrane protein 1) This gene encodes a high-affinity dickkopf homolog 1 (DKK1) transmembrane receptor that functionally cooperates with DKK1 to block wingless (WNT)/beta-catenin signaling. The encoded protein is a component of a membrane complex that modulates canonical WNT signaling through lipoprotein receptor-related protein 6 (LRP6). It contains extracellular kringle, WSC, and CUB domains. Mutations in this gene result in ectodermal dysplasia. This protein has also been found to be a functional receptor for Coxsackievirus A10 and may be an alternative entry receptor for SARS-CoV-2. [provided by RefSeq, Nov 2021]

C22orf31 (HGNC:26931): (chromosome 22 open reading frame 31)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06763536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KREMEN1	NM_001039570.3	c.82C>T	p.Leu28Phe	missense_variant	1/9	ENST00000400335.9	NP_001034659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KREMEN1	ENST00000400335.9	c.82C>T	p.Leu28Phe	missense_variant	1/9	1	NM_001039570.3	ENSP00000383189.4
KREMEN1	ENST00000407188.5	c.82C>T	p.Leu28Phe	missense_variant	1/9	1		ENSP00000385431.1
KREMEN1	ENST00000327813.9	c.82C>T	p.Leu28Phe	missense_variant	1/10	2		ENSP00000331242.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1032692 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 491086

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.82C>T (p.L28F) alteration is located in exon 1 (coding exon 1) of the KREMEN1 gene. This alteration results from a C to T substitution at nucleotide position 82, causing the leucine (L) at amino acid position 28 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	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	.;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.068	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.065
Sift	Benign	0.12	T;D;T
Sift4G	Uncertain	0.047	D;D;T
Polyphen		0.042	B;B;.
Vest4		0.11
MutPred		0.17		Loss of glycosylation at P30 (P = 0.1015);Loss of glycosylation at P30 (P = 0.1015);Loss of glycosylation at P30 (P = 0.1015);
MVP		0.34
MPC		0.35
ClinPred		0.21	T
GERP RS		-0.35
Varity_R		0.065
gMVP		0.38

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: chr22-29469200;