chr6-43450997-G-A

Variant names:

• chr6-43450997-G-A
• NM_023932.4:c.694C>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.694C>T​(p.His232Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DLK2 NM_023932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57
• 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: 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=0.2966109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DLK2	NM_023932.4	c.694C>T	p.His232Tyr	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.694C>T	p.His232Tyr	missense_variant	Exon 6 of 6	1	NM_023932.4	ENSP00000361566.3
DLK2	ENST00000357338.3	c.694C>T	p.His232Tyr	missense_variant	Exon 6 of 6	2		ENSP00000349893.3
DLK2	ENST00000372485.5	c.676C>T	p.His226Tyr	missense_variant	Exon 6 of 6	5		ENSP00000361563.1
DLK2	ENST00000430324.5	c.409C>T	p.His137Tyr	missense_variant	Exon 3 of 3	2		ENSP00000399829.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.694C>T (p.H232Y) alteration is located in exon 6 (coding exon 5) of the DLK2 gene. This alteration results from a C to T substitution at nucleotide position 694, causing the histidine (H) at amino acid position 232 to be replaced by a tyrosine (Y). 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	0.20
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;D;D
Eigen	Benign	0.00050
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.48	.;N;N
PhyloP100		2.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.97	.;D;D
Vest4		0.29
MutPred		0.52		.;Loss of disorder (P = 0.0786);Loss of disorder (P = 0.0786);
MVP		0.16
MPC		0.74
ClinPred		0.79	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.52
Mutation Taster		=92/8	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

hg19: chr6-43418735; COSMIC: COSV99767258; COSMIC: COSV99767258;