rs2303759

Positions:

• chr19-49365794-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014419.4(DKKL1):​c.326T>G​(p.Met109Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.27 in 1,613,050 control chromosomes in the GnomAD database, including 61,977 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (5717 hom., cov: 31)
  • Exomes 𝑓: 0.27 (56260 hom.)
• Consequence: DKKL1 NM_014419.4 missense, splice_region
• Scores: Splicing: ADA: 0.08543
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.02

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021131337).
• BP6: Variant 19-49365794-T-G is Benign according to our data. Variant chr19-49365794-T-G is described in ClinVar as [Benign]. Clinvar id is 1291174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.326T>G	p.Met109Arg	missense_variant, splice_region_variant	4/5	ENST00000221498.7	NP_055234.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DKKL1	ENST00000221498.7	c.326T>G	p.Met109Arg	missense_variant, splice_region_variant	4/5	1	NM_014419.4	ENSP00000221498	P1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40662 AN: 151886 Hom.: 5719 Cov.: 31

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.304

GnomAD3 exomes AF: 0.286 AC: 71596 AN: 250594 Hom.: 11026 AF XY: 0.298 AC XY: 40357 AN XY: 135410

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.271 AC: 395457 AN: 1461046 Hom.: 56260 Cov.: 35 AF XY: 0.278 AC XY: 201756 AN XY: 726808

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.335

Gnomad4 SAS exome AF: 0.459

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.278

GnomAD4 genome AF: 0.268 AC: 40680 AN: 152004 Hom.: 5717 Cov.: 31 AF XY: 0.265 AC XY: 19723 AN XY: 74322

Gnomad4 AFR AF: 0.280

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.153

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.306

Alfa AF: 0.272 Hom.: 14732

Bravo AF: 0.271

TwinsUK AF: 0.239 AC: 888

ALSPAC AF: 0.256 AC: 986

ESP6500AA AF: 0.287 AC: 1266

ESP6500EA AF: 0.265 AC: 2278

ExAC AF: 0.294 AC: 35721

Asia WGS AF: 0.395 AC: 1373 AN: 3478

EpiCase AF: 0.269

EpiControl AF: 0.283

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2020	This variant is associated with the following publications: (PMID: 21833088) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.62	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	.;N;.
MutationTaster	Benign	0.00014	P
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	.;D;.
REVEL	Benign	0.068
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.38	.;B;.
Vest4		0.14
MPC		0.41
ClinPred		0.030	T
GERP RS		4.3
Varity_R		0.87
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.085
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.19		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: rs2303759; hg19: chr19-49869051; COSMIC: COSV55561723; COSMIC: COSV55561723;