rs1054770

Variant names:

• chr19-49374858-G-A
• rs1054770
• NM_014419.4:c.559G>A

Variant summary

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

The NM_014419.4(DKKL1):​c.559G>A​(p.Gly187Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,613,496 control chromosomes in the GnomAD database, including 61,555 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.26 (5582 hom., cov: 31)
  • Exomes 𝑓: 0.27 (55973 hom.)
• Consequence: DKKL1 NM_014419.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• Publications: 31 publications found

Genes affected

DKKL1 (HGNC:16528): (dickkopf like acrosomal protein 1) The dickkopf protein family interacts with the Wnt signaling pathway and its members are characterized by two conserved cysteine-rich domains. This gene encodes a secreted protein that has low sequence similarity to the dickkopf-3 protein. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2010]

ENSG00000268686 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=3.1620264E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DKKL1	NM_014419.4	c.559G>A	p.Gly187Ser	missense_variant	Exon 5 of 5	ENST00000221498.7	NP_055234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DKKL1	ENST00000221498.7	c.559G>A	p.Gly187Ser	missense_variant	Exon 5 of 5	1	NM_014419.4	ENSP00000221498.1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40232 AN: 151914 Hom.: 5585 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.302

GnomAD2 exomes AF: 0.285 AC: 70661 AN: 248020 AF XY: 0.298

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.338

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.270 AC: 394583 AN: 1461464 Hom.: 55973 Cov.: 35 AF XY: 0.277 AC XY: 201332 AN XY: 727024

African (AFR) AF: 0.277 AC: 9271 AN: 33474

American (AMR) AF: 0.234 AC: 10462 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 8059 AN: 26124

East Asian (EAS) AF: 0.335 AC: 13291 AN: 39674

South Asian (SAS) AF: 0.457 AC: 39447 AN: 86226

European-Finnish (FIN) AF: 0.171 AC: 9107 AN: 53318

Middle Eastern (MID) AF: 0.421 AC: 2426 AN: 5768

European-Non Finnish (NFE) AF: 0.257 AC: 285800 AN: 1111838

Other (OTH) AF: 0.277 AC: 16720 AN: 60378

GnomAD4 genome AF: 0.265 AC: 40248 AN: 152032 Hom.: 5582 Cov.: 31 AF XY: 0.262 AC XY: 19499 AN XY: 74318

African (AFR) AF: 0.272 AC: 11276 AN: 41472

American (AMR) AF: 0.234 AC: 3575 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3470

East Asian (EAS) AF: 0.335 AC: 1724 AN: 5140

South Asian (SAS) AF: 0.456 AC: 2194 AN: 4814

European-Finnish (FIN) AF: 0.153 AC: 1618 AN: 10596

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17780 AN: 67944

Other (OTH) AF: 0.304 AC: 642 AN: 2110

Alfa AF: 0.271 Hom.: 9824

Bravo AF: 0.267

TwinsUK AF: 0.237 AC: 878

ALSPAC AF: 0.254 AC: 980

ESP6500AA AF: 0.276 AC: 1216

ESP6500EA AF: 0.261 AC: 2242

ExAC AF: 0.292 AC: 35447

Asia WGS AF: 0.395 AC: 1371 AN: 3478

EpiCase AF: 0.268

EpiControl AF: 0.282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.028
DANN	Benign	0.90
DEOGEN2	Benign	0.082	T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.50	T;T;T;T;T
MetaRNN	Benign	0.00032	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.77	.;.;N;.;.
PhyloP100		-1.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	.;.;N;.;.
REVEL	Benign	0.024
Sift	Benign	0.21	.;.;T;.;.
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.17	.;.;B;.;.
Vest4		0.024
MPC		0.15
ClinPred		0.0027	T
GERP RS		-3.2
Varity_R		0.034
gMVP		0.049
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: rs1054770; hg19: chr19-49878115; COSMIC: COSV55562509;