6-43450655-C-A

Position:

• chr6-43450655-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_023932.4(DLK2):​c.1036G>T​(p.Ala346Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DLK2 NM_023932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.215

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]

ABCC10 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05059275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DLK2	NM_023932.4	c.1036G>T	p.Ala346Ser	missense_variant	6/6	ENST00000372488.8	NP_076421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DLK2	ENST00000372488.8	c.1036G>T	p.Ala346Ser	missense_variant	6/6	1	NM_023932.4	ENSP00000361566.3
DLK2	ENST00000357338.3	c.1036G>T	p.Ala346Ser	missense_variant	6/6	2		ENSP00000349893.3
DLK2	ENST00000372485.5	c.1018G>T	p.Ala340Ser	missense_variant	6/6	5		ENSP00000361563.1
DLK2	ENST00000430324.5	c.751G>T	p.Ala251Ser	missense_variant	3/3	2		ENSP00000399829.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

DLK2: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.3
DANN	Benign	0.93
DEOGEN2	Benign	0.0064	T;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.66	T;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.46	.;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.28	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.14
MutPred		0.33		.;Gain of glycosylation at A346 (P = 0.0084);Gain of glycosylation at A346 (P = 0.0084);
MVP		0.41
MPC		0.29
ClinPred		0.041	T
GERP RS		-0.058
Varity_R		0.078
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-43418393;