6-43451096-G-C

Variant names:

• chr6-43451096-G-C
• rs149484687
• NM_023932.4:c.595C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_023932.4(DLK2):​c.595C>G​(p.Leu199Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,614,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DLK2 NM_023932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.071128786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK2	NM_023932.4	c.595C>G	p.Leu199Val	missense_variant	Exon 6 of 6	ENST00000372488.8	NP_076421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DLK2	ENST00000372488.8	c.595C>G	p.Leu199Val	missense_variant	Exon 6 of 6	1	NM_023932.4	ENSP00000361566.3
DLK2	ENST00000357338.3	c.595C>G	p.Leu199Val	missense_variant	Exon 6 of 6	2		ENSP00000349893.3
DLK2	ENST00000372485.5	c.577C>G	p.Leu193Val	missense_variant	Exon 6 of 6	5		ENSP00000361563.1
DLK2	ENST00000430324.5	c.310C>G	p.Leu104Val	missense_variant	Exon 3 of 3	2		ENSP00000399829.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 251346 AF XY: 0.000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.000136 AC XY: 99 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1112008

Other (OTH) AF: 0.000149 AC: 9 AN: 60396

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.0000939 AC XY: 7 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595C>G (p.L199V) 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 595, causing the leucine (L) at amino acid position 199 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Uncertain	-0.085	T
MutationAssessor	Benign	-0.085	.;N;N
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.065	.;B;B
Vest4		0.066
MVP		0.50
MPC		0.34
ClinPred		0.046	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.62
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs149484687; hg19: chr6-43418834;