rs575240044

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5BS2

The NM_178335.3(CCDC50):c.226C>T(p.Arg76Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.58

Variant links:

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]

CCDC50 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-191358112-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3 link	c.226C>T	p.Arg76Cys	missense_variant	Exon 3 of 12	ENST00000392455.9	NP_848018.1	Q8IVM0-2
CCDC50	NM_174908.4 link	c.226C>T	p.Arg76Cys	missense_variant	Exon 3 of 11		NP_777568.1	Q8IVM0-1
CCDC50	XM_011512460.2 link	c.226C>T	p.Arg76Cys	missense_variant	Exon 3 of 8		XP_011510762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9 link	c.226C>T	p.Arg76Cys	missense_variant	Exon 3 of 12	1	NM_178335.3	ENSP00000376249.4		Q8IVM0-2
CCDC50	ENST00000392456.4 link	c.226C>T	p.Arg76Cys	missense_variant	Exon 3 of 11	1		ENSP00000376250.4		Q8IVM0-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250994

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135642

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 12, 2017	Variant classified as Uncertain Significance - Favor Benign. The p.Arg76Cys vari ant in CCDC50 has been reported by our laboratory in one individual with hearing loss, which was inherited from an unaffected parent. It has been identified in 2/16512 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs575240044). Computational prediction tools an d conservation analysis suggest that the p.Arg76Cys variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Arg76Cys variant is uncert ain, its presence in an unaffected individual suggests that it is more likely to be benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 05, 2023	The c.226C>T (p.R76C) alteration is located in exon 3 (coding exon 3) of the CCDC50 gene. This alteration results from a C to T substitution at nucleotide position 226, causing the arginine (R) at amino acid position 76 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 14, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 76 of the CCDC50 protein (p.Arg76Cys). This variant is present in population databases (rs575240044, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CCDC50-related conditions. ClinVar contains an entry for this variant (Variation ID: 505396). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.094

.;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;D

Vest4

0.51

MVP

0.78

MPC

0.80

ClinPred

0.96

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.24

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over