19-49374858-G-A

Position:

• chr19-49374858-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
DKKL1	NM_014419.4	c.559G>A	p.Gly187Ser	missense_variant	5/5	ENST00000221498.7	NP_055234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKKL1	ENST00000221498.7	c.559G>A	p.Gly187Ser	missense_variant	5/5	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

GnomAD3 exomes AF: 0.285 AC: 70661 AN: 248020 Hom.: 10862 AF XY: 0.298 AC XY: 40041 AN XY: 134578

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 SAS exome AF: 0.456

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

Gnomad4 AFR exome AF: 0.277

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.335

Gnomad4 SAS exome AF: 0.457

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.277

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

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.304

Alfa AF: 0.268 Hom.: 6580

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;.;.
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

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

LitVar

Other links and lift over

dbSNP: rs1054770; hg19: chr19-49878115; COSMIC: COSV55562509;