16-46964741-T-C

Variant summary

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

The NM_005880.4(DNAJA2):ā€‹c.644A>Gā€‹(p.Lys215Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

DNAJA2
NM_005880.4 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.72
Variant links:
Genes affected
DNAJA2 (HGNC:14884): (DnaJ heat shock protein family (Hsp40) member A2) The protein encoded by this gene belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus; a glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain containing 4 motifs resembling a zinc finger domain. The product of this gene works as a cochaperone of Hsp70s in protein folding and mitochondrial protein import in vitro. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 UniProt
DNAJA2NM_005880.4 linkuse as main transcriptc.644A>G p.Lys215Arg missense_variant 6/9 ENST00000317089.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAJA2ENST00000317089.10 linkuse as main transcriptc.644A>G p.Lys215Arg missense_variant 6/91 NM_005880.4 P1
DNAJA2ENST00000617000.1 linkuse as main transcriptc.395A>G p.Lys132Arg missense_variant 4/42
DNAJA2ENST00000563158.1 linkuse as main transcriptc.*587A>G 3_prime_UTR_variant, NMD_transcript_variant 6/95

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461864
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 17, 2022The c.644A>G (p.K215R) alteration is located in exon 6 (coding exon 6) of the DNAJA2 gene. This alteration results from a A to G substitution at nucleotide position 644, causing the lysine (K) at amino acid position 215 to be replaced by an arginine (R). 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
Uncertain
0.39
BayesDel_addAF
Benign
-0.044
T
BayesDel_noAF
Benign
-0.30
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.28
T;T
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.031
D
MetaRNN
Uncertain
0.68
D;D
MetaSVM
Benign
-0.42
T
MutationAssessor
Uncertain
2.2
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-2.8
D;.
REVEL
Uncertain
0.33
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.011
D;.
Polyphen
1.0
D;.
Vest4
0.56
MutPred
0.54
Loss of methylation at K215 (P = 0.0098);.;
MVP
0.81
MPC
0.89
ClinPred
0.92
D
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.59
gMVP
0.54

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: chr16-46998653; API