chr6-43450883-C-G

Variant names:

• chr6-43450883-C-G
• rs1454844426
• NM_023932.4:c.808G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023932.4(DLK2):​c.808G>C​(p.Val270Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,078 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V270I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DLK2 NM_023932.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.747
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05292058).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK2	NM_023932.4	c.808G>C	p.Val270Leu	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.808G>C	p.Val270Leu	missense_variant	Exon 6 of 6	1	NM_023932.4	ENSP00000361566.3
DLK2	ENST00000357338.3	c.808G>C	p.Val270Leu	missense_variant	Exon 6 of 6	2		ENSP00000349893.3
DLK2	ENST00000372485.5	c.790G>C	p.Val264Leu	missense_variant	Exon 6 of 6	5		ENSP00000361563.1
DLK2	ENST00000430324.5	c.523G>C	p.Val175Leu	missense_variant	Exon 3 of 3	2		ENSP00000399829.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250236 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	4.1
DANN	Benign	0.75
DEOGEN2	Benign	0.017	T;T;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.59	T;.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.81	.;L;L
PhyloP100		0.75
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.65	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.057
MutPred		0.66		.;Gain of glycosylation at P266 (P = 0.1466);Gain of glycosylation at P266 (P = 0.1466);
MVP		0.043
MPC		0.31
ClinPred		0.021	T
GERP RS		1.3
Varity_R		0.041
gMVP		0.55
Mutation Taster		=93/7	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: rs1454844426; hg19: chr6-43418621;