chr6-43450973-T-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_023932.4(DLK2):c.718A>C(p.Ser240Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000458 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

DLK2
NM_023932.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.96

Publications

0 publications found

Variant links:

Genes affected

DLK2 (HGNC:21113): (delta like non-canonical Notch ligand 2) Predicted to enable Notch binding activity. Involved in negative regulation of Notch signaling pathway. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

DLK2 links:

ABCC10 (HGNC:52): (ATP binding cassette subfamily C member 10) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This ABC full-transporter is a member of the MRP subfamily which is involved in multi-drug resistance. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2010]

ABCC10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05670771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK2	NM_023932.4 link	c.718A>C	p.Ser240Arg	missense_variant	Exon 6 of 6	ENST00000372488.8	NP_076421.2	Q6UY11-1A0A024RD55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DLK2	ENST00000372488.8 link	c.718A>C	p.Ser240Arg	missense_variant	Exon 6 of 6	1	NM_023932.4	ENSP00000361566.3	Q6UY11-1
DLK2	ENST00000357338.3 link	c.718A>C	p.Ser240Arg	missense_variant	Exon 6 of 6	2		ENSP00000349893.3	Q6UY11-1
DLK2	ENST00000372485.5 link	c.700A>C	p.Ser234Arg	missense_variant	Exon 6 of 6	5		ENSP00000361563.1	Q5T3T9
DLK2	ENST00000430324.5 link	c.433A>C	p.Ser145Arg	missense_variant	Exon 3 of 3	2		ENSP00000399829.1	H0Y5P1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000478

AC:

AN:

251018

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112002

Other (OTH)

AF:

0.000182

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.718A>C (p.S240R) alteration is located in exon 6 (coding exon 5) of the DLK2 gene. This alteration results from a A to C substitution at nucleotide position 718, causing the serine (S) at amino acid position 240 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;T

Eigen

Benign

-0.039

Eigen_PC

Benign

0.097

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.82

T;.;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.057

T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.3

.;L;L

PhyloP100

5.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.55

N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.24

.;B;B

Vest4

0.23

MutPred

0.57

.;Loss of glycosylation at S240 (P = 0.0238);Loss of glycosylation at S240 (P = 0.0238);

MVP

0.21

MPC

0.68

ClinPred

0.21

GERP RS

3.6

Varity_R

0.12

gMVP

0.61

Mutation Taster

=91/9

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr6-43450973-T-G

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