22-29081853-T-G

Variant names:

• chr22-29081853-T-G
• rs20037
• NM_001039570.3:c.97+8626T>G

Variant summary

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

The NM_001039570.3(KREMEN1):​c.97+8626T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 152,024 control chromosomes in the GnomAD database, including 31,423 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 0.64 (31423 hom., cov: 32)
• Consequence: KREMEN1 NM_001039570.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0530
• Publications: 7 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039570.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KREMEN1	NM_001039570.3	MANE Select	c.97+8626T>G		intron	N/A	NP_001034659.2
	KREMEN1	NM_032045.5		c.97+8626T>G		intron	N/A	NP_114434.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KREMEN1	ENST00000400335.9	TSL:1 MANE Select	c.97+8626T>G		intron	N/A	ENSP00000383189.4
	KREMEN1	ENST00000407188.5	TSL:1	c.91+8632T>G		intron	N/A	ENSP00000385431.1
	KREMEN1	ENST00000327813.9	TSL:2	c.97+8626T>G		intron	N/A	ENSP00000331242.5

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97345 AN: 151906 Hom.: 31406 Cov.: 32

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.654

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

GnomAD4 genome AF: 0.641 AC: 97415 AN: 152024 Hom.: 31423 Cov.: 32 AF XY: 0.638 AC XY: 47408 AN XY: 74300

African (AFR) AF: 0.650 AC: 26936 AN: 41460

American (AMR) AF: 0.546 AC: 8332 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2565 AN: 3462

East Asian (EAS) AF: 0.574 AC: 2971 AN: 5172

South Asian (SAS) AF: 0.660 AC: 3181 AN: 4818

European-Finnish (FIN) AF: 0.654 AC: 6897 AN: 10548

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44262 AN: 67980

Other (OTH) AF: 0.652 AC: 1375 AN: 2110

Alfa AF: 0.650 Hom.: 15771

Bravo AF: 0.634

Asia WGS AF: 0.565 AC: 1968 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.8
DANN	Benign	0.71
PhyloP100		-0.053
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs20037; hg19: chr22-29477841;