12-49349285-C-T

Position:

• chr12-49349285-C-T

Variant summary

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

The NM_001304944.2(DNAJC22):​c.413C>T​(p.Ala138Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJC22 NM_001304944.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

Genes affected

DNAJC22 (HGNC:25802): (DnaJ heat shock protein family (Hsp40) member C22) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC22	NM_001304944.2	c.413C>T	p.Ala138Val	missense_variant	3/4	ENST00000549441.7	NP_001291873.1
DNAJC22	NM_024902.4	c.413C>T	p.Ala138Val	missense_variant	2/3		NP_079178.2
DNAJC22	XM_047429555.1	c.413C>T	p.Ala138Val	missense_variant	3/6		XP_047285511.1
DNAJC22	XM_047429556.1	c.413C>T	p.Ala138Val	missense_variant	3/5		XP_047285512.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC22	ENST00000549441.7	c.413C>T	p.Ala138Val	missense_variant	3/4	2	NM_001304944.2	ENSP00000446830.1
DNAJC22	ENST00000395069.3	c.413C>T	p.Ala138Val	missense_variant	2/3	1		ENSP00000378508.2
DNAJC22	ENST00000647553.1	n.413C>T		non_coding_transcript_exon_variant	2/4			ENSP00000498036.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2023

The c.413C>T (p.A138V) alteration is located in exon 2 (coding exon 1) of the DNAJC22 gene. This alteration results from a C to T substitution at nucleotide position 413, causing the alanine (A) at amino acid position 138 to be replaced by a valine (V). 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	0.24
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.99	D;D
Vest4		0.59
MutPred		0.34		Gain of catalytic residue at L140 (P = 3e-04);Gain of catalytic residue at L140 (P = 3e-04);
MVP		0.51
MPC		0.062
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1943743552; hg19: chr12-49743068;