17-35148382-C-T

Variant names:

• chr17-35148382-C-T
• NM_001267052.2:c.119C>T

Variant summary

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

The NM_001267052.2(UNC45B):​c.119C>T​(p.Ala40Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UNC45B NM_001267052.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18

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]

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 rank	MANE	Protein	UniProt
UNC45B	NM_001267052.2	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 20	ENST00000394570.7	NP_001253981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC45B	ENST00000394570.7	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 20	1	NM_001267052.2	ENSP00000378071.2
UNC45B	ENST00000591048.2	c.119C>T	p.Ala40Val	missense_variant	Exon 1 of 17	1		ENSP00000468335.1
UNC45B	ENST00000268876.9	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 20	5		ENSP00000268876.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.82	L;L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.11
Sift	Benign	0.18	T;T;.
Sift4G	Benign	0.12	T;T;T
Polyphen		0.19	B;B;P
Vest4		0.31
MutPred		0.36		Gain of methylation at K39 (P = 0.0407);Gain of methylation at K39 (P = 0.0407);Gain of methylation at K39 (P = 0.0407);
MVP		0.80
MPC		0.11
ClinPred		0.67	D
GERP RS		2.8
Varity_R		0.047
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.71		Position offset: -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: chr17-33475401;