rs2295660

Variant names:

• chr14-100734443-T-C
• rs2295660
• NM_003836.7:c.699T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

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
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.583
• Publications: 10 publications found

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]

ACMG classification

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003836.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLK1	NM_003836.7	MANE Select	c.699T>C	p.Cys233Cys	synonymous	Exon 5 of 5	NP_003827.4
	DLK1	NM_001317172.2		c.684+15T>C		intron	N/A	NP_001304101.2	P80370-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DLK1	ENST00000341267.9	TSL:1 MANE Select	c.699T>C	p.Cys233Cys	synonymous	Exon 5 of 5	ENSP00000340292.4	P80370-1
	DLK1	ENST00000331224.10	TSL:1	c.684+15T>C		intron	N/A	ENSP00000331081.6	P80370-2
	DLK1	ENST00000942991.1		c.699T>C	p.Cys233Cys	synonymous	Exon 6 of 6	ENSP00000613050.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1857 AN: 152142 Hom.: 27 Cov.: 32

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

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.: 33 AF XY: 0.00413 AC XY: 2997 AN XY: 726054

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: 2 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: 27 AN: 5762

European-Non Finnish (NFE) AF: 0.000508 AC: 564 AN: 1111208

Other (OTH) AF: 0.00774 AC: 467 AN: 60330

GnomAD4 genome AF: 0.0122 AC: 1856 AN: 152260 Hom.: 27 Cov.: 32 AF XY: 0.0131 AC XY: 973 AN XY: 74458

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: 0 AN: 3470

East Asian (EAS) AF: 0.0575 AC: 297 AN: 5168

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.0227 AC: 241 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 67994

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00425 Hom.: 15

Bravo AF: 0.0131

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	DLK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	10
DANN	Benign	0.72
PhyloP100		0.58
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2295660; hg19: chr14-101200780; COSMIC: COSV57991675; COSMIC: COSV57991675;