chr6-43451036-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_023932.4(DLK2):​c.655C>T​(p.Arg219Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,094 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 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DLK2
NM_023932.4 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.34781206).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DLK2NM_023932.4 linkc.655C>T p.Arg219Cys 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.655C>T p.Arg219Cys missense_variant Exon 6 of 6 1 NM_023932.4 ENSP00000361566.3 Q6UY11-1
DLK2ENST00000357338.3 linkc.655C>T p.Arg219Cys missense_variant Exon 6 of 6 2 ENSP00000349893.3 Q6UY11-1
DLK2ENST00000372485.5 linkc.637C>T p.Arg213Cys missense_variant Exon 6 of 6 5 ENSP00000361563.1 Q5T3T9
DLK2ENST00000430324.5 linkc.370C>T p.Arg124Cys missense_variant Exon 3 of 3 2 ENSP00000399829.1 H0Y5P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251184
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135814
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461868
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 08, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.655C>T (p.R219C) alteration is located in exon 6 (coding exon 5) of the DLK2 gene. This alteration results from a C to T substitution at nucleotide position 655, causing the arginine (R) at amino acid position 219 to be replaced by a cysteine (C). 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
Pathogenic
0.68
BayesDel_addAF
Uncertain
0.082
D
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D;D;D
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;.;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Uncertain
0.15
D
MutationAssessor
Benign
0.97
.;L;L
PrimateAI
Benign
0.41
T
PROVEAN
Benign
-2.3
N;N;N
REVEL
Uncertain
0.60
Sift
Benign
0.040
D;D;D
Sift4G
Uncertain
0.054
T;T;T
Polyphen
0.98
.;D;D
Vest4
0.21
MutPred
0.59
.;Loss of disorder (P = 0.0496);Loss of disorder (P = 0.0496);
MVP
0.35
MPC
1.0
ClinPred
0.90
D
GERP RS
4.9
Varity_R
0.20
gMVP
0.77

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: rs769492393; hg19: chr6-43418774; COSMIC: COSV55090098; COSMIC: COSV55090098; API