6-43450652-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_023932.4(DLK2):ā€‹c.1039C>Gā€‹(p.Pro347Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

DLK2
NM_023932.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1515257).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DLK2NM_023932.4 linkuse as main transcriptc.1039C>G p.Pro347Ala missense_variant 6/6 ENST00000372488.8 NP_076421.2 Q6UY11-1A0A024RD55

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DLK2ENST00000372488.8 linkuse as main transcriptc.1039C>G p.Pro347Ala missense_variant 6/61 NM_023932.4 ENSP00000361566.3 Q6UY11-1
DLK2ENST00000357338.3 linkuse as main transcriptc.1039C>G p.Pro347Ala missense_variant 6/62 ENSP00000349893.3 Q6UY11-1
DLK2ENST00000372485.5 linkuse as main transcriptc.1021C>G p.Pro341Ala missense_variant 6/65 ENSP00000361563.1 Q5T3T9
DLK2ENST00000430324.5 linkuse as main transcriptc.754C>G p.Pro252Ala missense_variant 3/32 ENSP00000399829.1 H0Y5P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461526
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727032
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:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74336
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:
0.0000147
Gnomad4 OTH
AF:
0.00
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 09, 2021The c.1039C>G (p.P347A) alteration is located in exon 6 (coding exon 5) of the DLK2 gene. This alteration results from a C to G substitution at nucleotide position 1039, causing the proline (P) at amino acid position 347 to be replaced by an alanine (A). 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
0.062
BayesDel_addAF
Uncertain
0.025
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0073
T;T;T
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.034
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.76
T;.;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
0.90
.;L;L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
0.070
N;N;N
REVEL
Benign
0.25
Sift
Benign
0.12
T;T;T
Sift4G
Benign
0.67
T;T;T
Polyphen
0.13
.;B;B
Vest4
0.26
MutPred
0.36
.;Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);
MVP
0.28
MPC
0.39
ClinPred
0.56
D
GERP RS
5.1
Varity_R
0.067
gMVP
0.17

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: rs1783661544; hg19: chr6-43418390; API