12-55822023-G-C

Variant names:

• chr12-55822023-G-C
• NM_032364.6:c.2063C>G

Variant summary

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

The NM_032364.6(DNAJC14):​c.2063C>G​(p.Ala688Gly) 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: 32)
• Consequence: DNAJC14 NM_032364.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

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=0.082645774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC14	NM_032364.6	c.2063C>G	p.Ala688Gly	missense_variant	Exon 7 of 7	ENST00000678005.2	NP_115740.5
ORMDL2	NM_014182.5	c.*1628G>C		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.2063C>G	p.Ala688Gly	missense_variant	Exon 7 of 7		NM_032364.6	ENSP00000504134.1
ENSG00000257390	ENST00000546837.5	c.950C>G	p.Ala317Gly	missense_variant	Exon 6 of 16	2		ENSP00000447000.1
ORMDL2	ENST00000243045.10	c.*1628G>C		downstream_gene_variant		1	NM_014182.5	ENSP00000243045.5

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 specified Uncertain:1

Mar 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2063C>G (p.A688G) alteration is located in exon 7 (coding exon 6) of the DNAJC14 gene. This alteration results from a C to G substitution at nucleotide position 2063, causing the alanine (A) at amino acid position 688 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;T;T
Eigen	Benign	0.059
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.67	T;.;.
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.063
Sift	Uncertain	0.0040	D;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.087	B;B;B
Vest4		0.13
MutPred		0.21		Gain of catalytic residue at K689 (P = 0.0145);Gain of catalytic residue at K689 (P = 0.0145);Gain of catalytic residue at K689 (P = 0.0145);
MVP		0.15
MPC		0.91
ClinPred		0.57	D
GERP RS		5.6
Varity_R		0.26
gMVP		0.10

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: chr12-56215807;