rs896068890

chr3-191375527-G-Cchr3-191375527-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178335.3(CCDC50):c.914G>C(p.Arg305Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CCDC50 NM_178335.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.322

Genes affected

CCDC50 (HGNC:18111): (coiled-coil domain containing 50) This gene encodes a soluble, cytoplasmic, tyrosine-phosphorylated protein with multiple ubiquitin-interacting domains. Mutations in this gene cause nonsyndromic, postlingual, progressive sensorineural DFNA44 hearing loss. In mouse, the protein is expressed in the inner ear during development and postnatal maturation and associates with microtubule-based structures. This protein may also function as a negative regulator of NF-kB signaling and as an effector of epidermal growth factor (EGF)-mediated cell signaling. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08917397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC50	NM_178335.3	c.914G>C	p.Arg305Thr	missense_variant	6/12	ENST00000392455.9
CCDC50	XM_011512460.2	c.914G>C	p.Arg305Thr	missense_variant	6/8
CCDC50	NM_174908.4	c.449-4632G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC50	ENST00000392455.9	c.914G>C	p.Arg305Thr	missense_variant	6/12	1	NM_178335.3	P3
CCDC50	ENST00000392456.4	c.449-4632G>C		intron_variant		1		A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 21, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Arg305Thr var iant in CCDC50 has not been previously reported in individuals with hearing loss or in large population studies. Arginine (Arg) at position 305 is not conserve d in mammals or evolutionarily distant species and 1 mammal (star-nosed mole) ca rries a threonine (Thr) at the position, supporting that this change may be tole rated. Additional computational prediction tools suggest that the p.Arg305Thr v ariant may not impact the protein, though this information is not predictive eno ugh to rule out pathogenicity. In summary, while the clinical significance of th e p.Arg305Thr variant is uncertain, these data suggest that it is more likely to be benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 504928). This variant has not been reported in the literature in individuals affected with CCDC50-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with threonine at codon 305 of the CCDC50 protein (p.Arg305Thr). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Benign	0.96
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.30	T
Polyphen		0.40	B
MutPred		0.20		Loss of glycosylation at P308 (P = 0.0176);
ClinPred		0.99	D
GERP RS		3.0
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs896068890; hg19: chr3-191093316;