chr6-43450804-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_023932.4(DLK2):​c.887G>A​(p.Arg296Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,614,088 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 1 hom. )

Consequence

DLK2
NM_023932.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.037432015).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DLK2NM_023932.4 linkc.887G>A p.Arg296Gln missense_variant Exon 6 of 6 ENST00000372488.8 NP_076421.2 Q6UY11-1A0A024RD55

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DLK2ENST00000372488.8 linkc.887G>A p.Arg296Gln missense_variant Exon 6 of 6 1 NM_023932.4 ENSP00000361566.3 Q6UY11-1
DLK2ENST00000357338.3 linkc.887G>A p.Arg296Gln missense_variant Exon 6 of 6 2 ENSP00000349893.3 Q6UY11-1
DLK2ENST00000372485.5 linkc.869G>A p.Arg290Gln missense_variant Exon 6 of 6 5 ENSP00000361563.1 Q5T3T9
DLK2ENST00000430324.5 linkc.602G>A p.Arg201Gln missense_variant Exon 3 of 3 2 ENSP00000399829.1 H0Y5P1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000152
AC:
38
AN:
250806
Hom.:
1
AF XY:
0.000140
AC XY:
19
AN XY:
135600
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00139
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000106
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000876
AC:
128
AN:
1461870
Hom.:
1
Cov.:
31
AF XY:
0.000100
AC XY:
73
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00107
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000197
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000558
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000203
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.887G>A (p.R296Q) 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 887, causing the arginine (R) at amino acid position 296 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
0.089
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.0088
T;T;T
Eigen
Benign
0.088
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.95
D;.;D
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.037
T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Benign
0.97
.;L;L
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-0.19
N;N;N
REVEL
Benign
0.24
Sift
Benign
0.36
T;T;T
Sift4G
Benign
0.42
T;T;T
Polyphen
0.96
.;D;D
Vest4
0.13
MVP
0.52
MPC
0.70
ClinPred
0.087
T
GERP RS
5.1
Varity_R
0.10
gMVP
0.43

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

LitVar

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

Other links and lift over

dbSNP: rs200707852; hg19: chr6-43418542; API