12-49349166-C-G

Variant names:

• chr12-49349166-C-G
• rs769518529
• NM_001304944.2:c.294C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001304944.2(DNAJC22):​c.294C>G​(p.Ser98Arg) 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 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJC22 NM_001304944.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304944.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC22	NM_001304944.2	MANE Select	c.294C>G	p.Ser98Arg	missense	Exon 3 of 4	NP_001291873.1	Q8N4W6
	DNAJC22	NM_024902.4		c.294C>G	p.Ser98Arg	missense	Exon 2 of 3	NP_079178.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC22	ENST00000549441.7	TSL:2 MANE Select	c.294C>G	p.Ser98Arg	missense	Exon 3 of 4	ENSP00000446830.1	Q8N4W6
	DNAJC22	ENST00000395069.3	TSL:1	c.294C>G	p.Ser98Arg	missense	Exon 2 of 3	ENSP00000378508.2	Q8N4W6
	DNAJC22	ENST00000851339.1		c.294C>G	p.Ser98Arg	missense	Exon 4 of 5	ENSP00000521398.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.063
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.068	T
Polyphen		0.66	P
Vest4		0.65
MutPred		0.61		Gain of catalytic residue at L93 (P = 9e-04)
MVP		0.29
MPC		0.080
ClinPred		0.93	D
GERP RS		2.1
Varity_R		0.23
gMVP		0.95
Mutation Taster		=71/29	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

dbSNP: rs769518529; hg19: chr12-49742949;