19-49374796-G-A

Position:

• chr19-49374796-G-A

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.497G>A​(p.Arg166Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,612,164 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (70 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (59 hom.)
• Consequence: DKKL1 NM_014419.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.797

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001806289).
• BP6: Variant 19-49374796-G-A is Benign according to our data. Variant chr19-49374796-G-A is described in ClinVar as [Benign]. Clinvar id is 780579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DKKL1	NM_014419.4	c.497G>A	p.Arg166Gln	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.497G>A	p.Arg166Gln	missense_variant	5/5	1	NM_014419.4	ENSP00000221498.1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2326 AN: 152118 Hom.: 70 Cov.: 31

Gnomad AFR AF: 0.0515

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00438 AC: 1087 AN: 248082 Hom.: 28 AF XY: 0.00339 AC XY: 456 AN XY: 134360

Gnomad AFR exome AF: 0.0529

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000198

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00234 AC: 3418 AN: 1459928 Hom.: 59 Cov.: 30 AF XY: 0.00211 AC XY: 1532 AN XY: 726050

Gnomad4 AFR exome AF: 0.0551

Gnomad4 AMR exome AF: 0.00310

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.0153 AC: 2329 AN: 152236 Hom.: 70 Cov.: 31 AF XY: 0.0148 AC XY: 1102 AN XY: 74440

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.00680

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00352 Hom.: 15

Bravo AF: 0.0180

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0515 AC: 227

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00556 AC: 675

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000534

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 30, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;T;T;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.77	T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	.;.;L;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.75	.;.;N;.;.
REVEL	Benign	0.064
Sift	Uncertain	0.0050	.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.58	.;.;P;.;.
Vest4		0.14
MVP		0.061
MPC		0.19
ClinPred		0.017	T
GERP RS		0.60
Varity_R		0.075
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111233735; hg19: chr19-49878053;