10-52316550-G-A

Variant names:

• chr10-52316550-G-A
• rs183951849
• NM_012242.4:c.548-4G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_012242.4(DKK1):​c.548-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,613,576 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (12 hom.)
• Consequence: DKK1 NM_012242.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001591
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16
• Publications: 1 publications found

Genes affected

DKK1 (HGNC:2891): (dickkopf WNT signaling pathway inhibitor 1) This gene encodes a member of the dickkopf family of proteins. Members of this family are secreted proteins characterized by two cysteine-rich domains that mediate protein-protein interactions. The encoded protein binds to the LRP6 co-receptor and inhibits beta-catenin-dependent Wnt signaling. This gene plays a role in embryonic development and may be important in bone formation in adults. Elevated expression of this gene has been observed in numerous human cancers and this protein may promote proliferation, invasion and growth in cancer cell lines. [provided by RefSeq, Sep 2017]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-52316550-G-A is Benign according to our data. Variant chr10-52316550-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 773234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 571 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012242.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKK1	NM_012242.4	MANE Select	c.548-4G>A		splice_region intron	N/A	NP_036374.1	I1W660

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DKK1	ENST00000373970.4	TSL:1 MANE Select	c.548-4G>A		splice_region intron	N/A	ENSP00000363081.3	O94907
	DKK1	ENST00000476752.1	TSL:2	n.197-4G>A		splice_region intron	N/A
	DKK1	ENST00000494277.5	TSL:5	n.171-4G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 571 AN: 152078 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00355 AC: 890 AN: 250922 AF XY: 0.00358

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.00467

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00322 AC: 4704 AN: 1461380 Hom.: 12 Cov.: 33 AF XY: 0.00329 AC XY: 2389 AN XY: 726946

African (AFR) AF: 0.000329 AC: 11 AN: 33470

American (AMR) AF: 0.000582 AC: 26 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00280 AC: 73 AN: 26116

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86184

European-Finnish (FIN) AF: 0.0141 AC: 753 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00329 AC: 3653 AN: 1111820

Other (OTH) AF: 0.00295 AC: 178 AN: 60378

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152196 Hom.: 6 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74410

African (AFR) AF: 0.000578 AC: 24 AN: 41522

American (AMR) AF: 0.000196 AC: 3 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00428 Hom.: 2

Bravo AF: 0.00206

EpiCase AF: 0.00311

EpiControl AF: 0.00290

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.70
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.012
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: rs183951849; hg19: chr10-54076310;