rs149448438

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_023932.4(DLK2):c.1091C>A(p.Pro364Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,598,712 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

DLK2
NM_023932.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

Publications

3 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.11725047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK2	NM_023932.4 link	c.1091C>A	p.Pro364Gln	missense_variant	Exon 6 of 6	ENST00000372488.8	NP_076421.2	Q6UY11-1A0A024RD55
ABCC10	NM_001198934.2 link	c.*509G>T		downstream_gene_variant		ENST00000372530.9	NP_001185863.1	Q5T3U5-1A0A024RD21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLK2	ENST00000372488.8 link	c.1091C>A	p.Pro364Gln	missense_variant	Exon 6 of 6	1	NM_023932.4	ENSP00000361566.3		Q6UY11-1
ABCC10	ENST00000372530.9 link	c.*509G>T		downstream_gene_variant		2	NM_001198934.2	ENSP00000361608.4		Q5T3U5-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000181

AC:

AN:

237950

AF XY:

0.000171

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000319

Gnomad OTH exome

AF:

0.000519

GnomAD4 exome

AF:

0.000238

AC:

345

AN:

1446616

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

144

AN XY:

717512

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33312

American (AMR)

AF:

0.000159

AC:

AN:

43978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24974

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

84344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.000296

AC:

326

AN:

1102714

Other (OTH)

AF:

0.000168

AC:

AN:

59628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000145

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41424

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1091C>A (p.P364Q) alteration is located in exon 6 (coding exon 5) of the DLK2 gene. This alteration results from a C to A substitution at nucleotide position 1091, causing the proline (P) at amino acid position 364 to be replaced by a glutamine (Q). 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

0.12

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0077

T;T;T

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.58

T;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

.;L;L

PhyloP100

2.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.22

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.18

T;T;T

Sift4G

Uncertain

0.023

D;D;D

Polyphen

0.0010

.;B;B

Vest4

0.35

MVP

0.24

MPC

0.36

ClinPred

0.024

GERP RS

5.1

Varity_R

0.040

gMVP

0.22

Mutation Taster

=93/7

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

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rs149448438

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