22-29129138-C-T

Variant names:

• chr22-29129138-C-T
• rs132274
• NM_001039570.3:c.631+3722C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001039570.3(KREMEN1):​c.631+3722C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 151,916 control chromosomes in the GnomAD database, including 24,176 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (24176 hom., cov: 31)
• Consequence: KREMEN1 NM_001039570.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.338
• Publications: 5 publications found

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]

KREMEN1 Gene-Disease associations (from GenCC):

• ectodermal dysplasia 13, hair/tooth type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KREMEN1	NM_001039570.3	c.631+3722C>T		intron_variant	Intron 5 of 8	ENST00000400335.9	NP_001034659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KREMEN1	ENST00000400335.9	c.631+3722C>T		intron_variant	Intron 5 of 8	1	NM_001039570.3	ENSP00000383189.4
KREMEN1	ENST00000407188.5	c.625+3722C>T		intron_variant	Intron 5 of 8	1		ENSP00000385431.1

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80677 AN: 151798 Hom.: 24177 Cov.: 31

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.598

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.531 AC: 80676 AN: 151916 Hom.: 24176 Cov.: 31 AF XY: 0.530 AC XY: 39341 AN XY: 74266

African (AFR) AF: 0.237 AC: 9810 AN: 41460

American (AMR) AF: 0.646 AC: 9856 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2416 AN: 3470

East Asian (EAS) AF: 0.672 AC: 3467 AN: 5162

South Asian (SAS) AF: 0.617 AC: 2965 AN: 4806

European-Finnish (FIN) AF: 0.555 AC: 5852 AN: 10536

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.653 AC: 44332 AN: 67934

Other (OTH) AF: 0.597 AC: 1257 AN: 2104

Alfa AF: 0.624 Hom.: 133637

Bravo AF: 0.527

Asia WGS AF: 0.579 AC: 2009 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.79
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs132274; hg19: chr22-29525126;