Genetic Variant DLK2:p.Gly243Asp (chr6-43450963-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_023932.4(DLK2):c.728G>A(p.Gly243Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G243A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DLK2
NM_023932.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.34

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37660924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK2	NM_023932.4 link	c.728G>A	p.Gly243Asp	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.728G>A	p.Gly243Asp	missense_variant	Exon 6 of 6	1	NM_023932.4	ENSP00000361566.3	Q6UY11-1
DLK2	ENST00000357338.3 link	c.728G>A	p.Gly243Asp	missense_variant	Exon 6 of 6	2		ENSP00000349893.3	Q6UY11-1
DLK2	ENST00000372485.5 link	c.710G>A	p.Gly237Asp	missense_variant	Exon 6 of 6	5		ENSP00000361563.1	Q5T3T9
DLK2	ENST00000430324.5 link	c.443G>A	p.Gly148Asp	missense_variant	Exon 3 of 3	2		ENSP00000399829.1	H0Y5P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00000138

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:

0.00

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:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;.;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.39

.;N;N

PhyloP100

3.3

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.75

N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.62

T;T;T

Polyphen

0.99

.;D;D

Vest4

0.36

MutPred

0.39

.;Loss of methylation at K245 (P = 0.0654);Loss of methylation at K245 (P = 0.0654);

MVP

0.26

MPC

0.55

ClinPred

0.75

GERP RS

4.9

Varity_R

0.095

gMVP

0.77

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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chr6-43450963-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over