dbSNP rs2295660: DLK1:p.Cys233Cys (chr14-100734443-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_003836.7(DLK1):c.699T>C(p.Cys233Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,612,072 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.012 ( 27 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 143 hom. )

Consequence

DLK1
NM_003836.7 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.583

Publications

10 publications found

Variant links:

Genes affected

DLK1 (HGNC:2907): (delta like non-canonical Notch ligand 1) This gene encodes a transmembrane protein that contains multiple epidermal growth factor repeats that functions as a regulator of cell growth. The encoded protein is involved in the differentiation of several cell types including adipocytes. This gene is located in a region of chromosome 14 frequently showing unparental disomy, and is imprinted and expressed from the paternal allele. A single nucleotide variant in this gene is associated with child and adolescent obesity and shows polar overdominance, where heterozygotes carrying an active paternal allele express the phenotype, while mutant homozygotes are normal. [provided by RefSeq, Nov 2015]

DLK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 14-100734443-T-C is Benign according to our data. Variant chr14-100734443-T-C is described in ClinVar as [Benign]. Clinvar id is 3037935.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.583 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK1	NM_003836.7 link	c.699T>C	p.Cys233Cys	synonymous_variant	Exon 5 of 5	ENST00000341267.9	NP_003827.4	P80370-1A0A024R6L1A8K019
DLK1	NM_001317172.2 link	c.684+15T>C		intron_variant	Intron 5 of 5		NP_001304101.2	P80370-2A8K019

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLK1	ENST00000341267.9 link	c.699T>C	p.Cys233Cys	synonymous_variant	Exon 5 of 5	1	NM_003836.7	ENSP00000340292.4		P80370-1
DLK1	ENST00000331224.10 link	c.684+15T>C		intron_variant	Intron 5 of 5	1		ENSP00000331081.6		P80370-2

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1857

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0581

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.0108

AC:

2689

AN:

249398

AF XY:

0.00946

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.0129

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.0617

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.00804

GnomAD4 exome

AF:

0.00427

AC:

6232

AN:

1459812

Hom.:

143

Cov.:

AF XY:

0.00413

AC XY:

2997

AN XY:

726054

show subpopulations

African (AFR)

AF:

0.0261

AC:

873

AN:

33458

American (AMR)

AF:

0.0119

AC:

531

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26108

East Asian (EAS)

AF:

0.0667

AC:

2647

AN:

39662

South Asian (SAS)

AF:

0.00232

AC:

200

AN:

86204

European-Finnish (FIN)

AF:

0.0176

AC:

921

AN:

52406

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000508

AC:

564

AN:

1111208

Other (OTH)

AF:

0.00774

AC:

467

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

409

819

1228

1638

2047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<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:

0.0122

AC:

1856

AN:

152260

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

973

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0248

AC:

1029

AN:

41550

American (AMR)

AF:

0.0138

AC:

211

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0575

AC:

297

AN:

5168

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0227

AC:

241

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

67994

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

100

201

301

402

502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00425

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DLK1-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

0.58

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over