6-43450618-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_023932.4(DLK2):​c.1073G>A​(p.Cys358Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

DLK2
NM_023932.4 missense

Scores

7
5
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DLK2NM_023932.4 linkc.1073G>A p.Cys358Tyr missense_variant Exon 6 of 6 ENST00000372488.8 NP_076421.2 Q6UY11-1A0A024RD55
ABCC10NM_001198934.2 linkc.*527C>T downstream_gene_variant ENST00000372530.9 NP_001185863.1 Q5T3U5-1A0A024RD21

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DLK2ENST00000372488.8 linkc.1073G>A p.Cys358Tyr missense_variant Exon 6 of 6 1 NM_023932.4 ENSP00000361566.3 Q6UY11-1
ABCC10ENST00000372530.9 linkc.*527C>T downstream_gene_variant 2 NM_001198934.2 ENSP00000361608.4 Q5T3U5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 10, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1073G>A (p.C358Y) alteration is located in exon 6 (coding exon 5) of the DLK2 gene. This alteration results from a G to A substitution at nucleotide position 1073, causing the cysteine (C) at amino acid position 358 to be replaced by a tyrosine (Y). 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
Uncertain
0.36
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.071
T;T;T
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.82
T;.;T
M_CAP
Benign
0.077
D
MetaRNN
Uncertain
0.61
D;D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.0
.;L;L
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-2.0
N;N;N
REVEL
Pathogenic
0.72
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.72
MutPred
0.51
.;Gain of phosphorylation at C358 (P = 0.0078);Gain of phosphorylation at C358 (P = 0.0078);
MVP
0.78
MPC
1.4
ClinPred
0.97
D
GERP RS
5.1
Varity_R
0.82
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1347202079; hg19: chr6-43418356; API