rs147604673

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_178335.3(CCDC50):c.1396C>T(p.Arg466Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,613,704 control chromosomes in the GnomAD database, including 334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 27 hom., cov: 32)

Exomes 𝑓: 0.019 ( 307 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.91

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 44
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CCDC50 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045622587).

BP6

Variant 3-191389569-C-T is Benign according to our data. Variant chr3-191389569-C-T is described in ClinVar as Benign. ClinVar VariationId is 48152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0135 (2055/152234) while in subpopulation NFE AF = 0.0202 (1377/68028). AF 95% confidence interval is 0.0194. There are 27 homozygotes in GnomAd4. There are 989 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2055 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3 link	c.1396C>T	p.Arg466Trp	missense_variant	Exon 11 of 12	ENST00000392455.9	NP_848018.1	Q8IVM0-2
CCDC50	NM_174908.4 link	c.868C>T	p.Arg290Trp	missense_variant	Exon 10 of 11		NP_777568.1	Q8IVM0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9 link	c.1396C>T	p.Arg466Trp	missense_variant	Exon 11 of 12	1	NM_178335.3	ENSP00000376249.4		Q8IVM0-2
CCDC50	ENST00000392456.4 link	c.868C>T	p.Arg290Trp	missense_variant	Exon 10 of 11	1		ENSP00000376250.4		Q8IVM0-1

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2058

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00714

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0285

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0203

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0146

AC:

3665

AN:

251358

AF XY:

0.0151

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0256

Gnomad NFE exome

AF:

0.0205

Gnomad OTH exome

AF:

0.0150

GnomAD4 exome

AF:

0.0189

AC:

27685

AN:

1461470

Hom.:

307

Cov.:

AF XY:

0.0189

AC XY:

13715

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

33474

American (AMR)

AF:

0.00523

AC:

234

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

288

AN:

26132

East Asian (EAS)

AF:

0.000529

AC:

AN:

39686

South Asian (SAS)

AF:

0.0121

AC:

1042

AN:

86254

European-Finnish (FIN)

AF:

0.0256

AC:

1369

AN:

53414

Middle Eastern (MID)

AF:

0.0121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0211

AC:

23494

AN:

1111644

Other (OTH)

AF:

0.0182

AC:

1101

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1271

2542

3812

5083

6354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

866

1732

2598

3464

4330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0135

AC:

2055

AN:

152234

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

989

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41522

American (AMR)

AF:

0.00713

AC:

109

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.0143

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0285

AC:

302

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0202

AC:

1377

AN:

68028

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

112

223

335

446

558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0171

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0215

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0215

AC:

185

ExAC

AF:

0.0154

AC:

1864

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0191

EpiControl

AF:

0.0171

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg466Trp in Exon 11 of CCDC50: This variant is not expected to have clinical si gnificance because it has been identified in 2.3% (161/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs147604673). -

Nov 16, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 12, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nonsyndromic genetic hearing loss

Benign:1

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T

Eigen

Benign

0.067

Eigen_PC

Benign

0.015

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

1.9

PrimateAI

Uncertain

0.48

REVEL

Benign

0.12

Polyphen

0.31

B;D

MPC

0.70

ClinPred

0.030

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.093

gMVP

0.12

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over