17-35180636-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001267052.2(UNC45B):​c.2333C>G​(p.Ala778Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A778V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

UNC45B
NM_001267052.2 missense

Scores

6
11
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.80
Variant links:
Genes affected
UNC45B (HGNC:14304): (unc-45 myosin chaperone B) This gene encodes a co-chaperone required for folding and accumulation of type II myosins. The protein consists of three tetratricopeptide repeat motifs at the N-terminus that form a complex with heat shock protein 90, a central region of unknown function that is conserved in all Unc-45 proteins, and a C-terminal Unc-45/Cro1/She4 domain. The protein is expressed at high levels in striated muscle, where its muscle myosin chaperone activity is dependent on heat shock protein 90 acting as a co-chaperone. A missense mutation in this gene has been associated with cataract development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
UNC45BNM_001267052.2 linkuse as main transcriptc.2333C>G p.Ala778Gly missense_variant 18/20 ENST00000394570.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UNC45BENST00000394570.7 linkuse as main transcriptc.2333C>G p.Ala778Gly missense_variant 18/201 NM_001267052.2 P4Q8IWX7-3
UNC45BENST00000591048.2 linkuse as main transcriptc.2096C>G p.Ala699Gly missense_variant 15/171 Q8IWX7-2
UNC45BENST00000268876.9 linkuse as main transcriptc.2339C>G p.Ala780Gly missense_variant 18/205 A1Q8IWX7-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D;.;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Benign
0.067
D
MetaRNN
Pathogenic
0.83
D;D;D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Pathogenic
3.3
M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-3.5
D;.;.
REVEL
Uncertain
0.51
Sift
Uncertain
0.0050
D;.;.
Sift4G
Uncertain
0.013
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.80
MVP
0.86
MPC
0.50
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.52
gMVP
0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs577155361; hg19: chr17-33507655; API