chr19-49365794-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/23 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 (★★).

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

Publications

95 publications found

Variant links:

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]

DKKL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014419.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DKKL1	NM_014419.4	MANE Select	c.326T>G	p.Met109Arg	missense splice_region	Exon 4 of 5	NP_055234.1
DKKL1	NM_001197302.2		c.101T>G	p.Met34Arg	missense splice_region	Exon 4 of 5	NP_001184231.1
DKKL1	NM_001197301.2		c.324+145T>G		intron	N/A	NP_001184230.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DKKL1	ENST00000221498.7	TSL:1 MANE Select	c.326T>G	p.Met109Arg	missense splice_region	Exon 4 of 5	ENSP00000221498.1
DKKL1	ENST00000597873.5	TSL:3	c.101T>G	p.Met34Arg	missense splice_region	Exon 4 of 5	ENSP00000472866.1
DKKL1	ENST00000596402.1	TSL:3	c.101T>G	p.Met34Arg	missense splice_region	Exon 4 of 5	ENSP00000470676.1

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40662

AN:

151886

Hom.:

5719

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.286

AC:

71596

AN:

250594

AF XY:

0.298

show subpopulations

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 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.:

AF XY:

0.278

AC XY:

201756

AN XY:

726808

show subpopulations

African (AFR)

AF:

0.285

AC:

9540

AN:

33460

American (AMR)

AF:

0.234

AC:

10462

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

8054

AN:

26110

East Asian (EAS)

AF:

0.335

AC:

13296

AN:

39686

South Asian (SAS)

AF:

0.459

AC:

39503

AN:

86136

European-Finnish (FIN)

AF:

0.171

AC:

9124

AN:

53406

Middle Eastern (MID)

AF:

0.422

AC:

2436

AN:

5766

European-Non Finnish (NFE)

AF:

0.258

AC:

286263

AN:

1111478

Other (OTH)

AF:

0.278

AC:

16779

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

13596

27192

40787

54383

67979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9720

19440

29160

38880

48600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.268

AC:

40680

AN:

152004

Hom.:

5717

Cov.:

AF XY:

0.265

AC XY:

19723

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.280

AC:

11619

AN:

41460

American (AMR)

AF:

0.236

AC:

3600

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.322

AC:

1117

AN:

3470

East Asian (EAS)

AF:

0.338

AC:

1739

AN:

5146

South Asian (SAS)

AF:

0.456

AC:

2198

AN:

4818

European-Finnish (FIN)

AF:

0.153

AC:

1625

AN:

10594

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.262

AC:

17817

AN:

67946

Other (OTH)

AF:

0.306

AC:

644

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1509

3019

4528

6038

7547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.270

Hom.:

28555

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Apr 27, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21833088)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.053

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

PhyloP100

4.0

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.068

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

0.38

Vest4

0.14

MPC

0.41

ClinPred

0.030

GERP RS

4.3

Varity_R

0.87

gMVP

0.33

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over