NM_001267052.2:c.2407C>G

Variant names:

• chr17-35183460-C-G
• rs370424081
• NM_001267052.2:c.2407C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001267052.2(UNC45B):​c.2407C>G​(p.Arg803Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,386 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R803W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UNC45B NM_001267052.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 5 publications found

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]

UNC45B Gene-Disease associations (from GenCC):

• myofibrillar myopathy 11

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cataract 43

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-35183460-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 187851.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC45B	NM_001267052.2	c.2407C>G	p.Arg803Gly	missense_variant	Exon 19 of 20	ENST00000394570.7	NP_001253981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC45B	ENST00000394570.7	c.2407C>G	p.Arg803Gly	missense_variant	Exon 19 of 20	1	NM_001267052.2	ENSP00000378071.2
UNC45B	ENST00000591048.2	c.2170C>G	p.Arg724Gly	missense_variant	Exon 16 of 17	1		ENSP00000468335.1
UNC45B	ENST00000268876.9	c.2413C>G	p.Arg805Gly	missense_variant	Exon 19 of 20	5		ENSP00000268876.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446386 Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2 AN XY: 719408

⚠️ 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: 32944

American (AMR) AF: 0.00 AC: 0 AN: 42730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25508

East Asian (EAS) AF: 0.00 AC: 0 AN: 38876

South Asian (SAS) AF: 0.00 AC: 0 AN: 83960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104084

Other (OTH) AF: 0.0000168 AC: 1 AN: 59572

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001943), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	2.9	M;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;P
Vest4		0.86
MutPred		0.66		Loss of ubiquitination at K807 (P = 0.0747);.;.;
MVP		0.80
MPC		0.37
ClinPred		0.99	D
GERP RS		1.8
Varity_R		0.81
gMVP		0.69

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: rs370424081; hg19: chr17-33510479;