chr6-43451096-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023932.4(DLK2):​c.595C>T​(p.Leu199Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. L199V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLK2 NM_023932.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40530795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK2	NM_023932.4	c.595C>T	p.Leu199Phe	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>T	p.Leu199Phe	missense_variant	Exon 6 of 6	1	NM_023932.4	ENSP00000361566.3
DLK2	ENST00000357338.3	c.595C>T	p.Leu199Phe	missense_variant	Exon 6 of 6	2		ENSP00000349893.3
DLK2	ENST00000372485.5	c.577C>T	p.Leu193Phe	missense_variant	Exon 6 of 6	5		ENSP00000361563.1
DLK2	ENST00000430324.5	c.310C>T	p.Leu104Phe	missense_variant	Exon 3 of 3	2		ENSP00000399829.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T;.;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.5	.;L;L
PhyloP100		1.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.066	T;T;T
Polyphen		0.93	.;P;P
Vest4		0.13
MutPred		0.41		.;Loss of catalytic residue at L199 (P = 0.1436);Loss of catalytic residue at L199 (P = 0.1436);
MVP		0.53
MPC		0.84
ClinPred		0.73	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.68
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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;