12-55822046-G-T

Variant names:

• chr12-55822046-G-T
• rs994564021
• NM_032364.6:c.2040C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032364.6(DNAJC14):​c.2040C>A​(p.Asn680Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJC14 NM_032364.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

Genes affected

DNAJC14 (HGNC:24581): (DnaJ heat shock protein family (Hsp40) member C14) Predicted to be involved in protein transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000257390 (HGNC:):

ORMDL2 (HGNC:16037): (ORMDL sphingolipid biosynthesis regulator 2) Involved in ceramide metabolic process. Acts upstream of or within negative regulation of ceramide biosynthetic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0918636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC14	NM_032364.6	c.2040C>A	p.Asn680Lys	missense_variant	Exon 7 of 7	ENST00000678005.2	NP_115740.5
ORMDL2	NM_014182.5	c.*1651G>T		downstream_gene_variant		ENST00000243045.10	NP_054901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC14	ENST00000678005.2	c.2040C>A	p.Asn680Lys	missense_variant	Exon 7 of 7		NM_032364.6	ENSP00000504134.1
ENSG00000257390	ENST00000546837.5	c.927C>A	p.Asn309Lys	missense_variant	Exon 6 of 16	2		ENSP00000447000.1
ORMDL2	ENST00000243045.10	c.*1651G>T		downstream_gene_variant		1	NM_014182.5	ENSP00000243045.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2040C>A (p.N680K) alteration is located in exon 7 (coding exon 6) of the DNAJC14 gene. This alteration results from a C to A substitution at nucleotide position 2040, causing the asparagine (N) at amino acid position 680 to be replaced by a lysine (K). 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	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.078	T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;.;.
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.0060
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.049	B;B;B
Vest4		0.074
MutPred		0.32		Gain of catalytic residue at K678 (P = 0.0041);Gain of catalytic residue at K678 (P = 0.0041);Gain of catalytic residue at K678 (P = 0.0041);
MVP		0.13
MPC		0.94
ClinPred		0.21	T
GERP RS		1.8
Varity_R		0.11
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs994564021; hg19: chr12-56215830;