rs35380043

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.363A>T(p.Leu121Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,612,876 control chromosomes in the GnomAD database, including 1,634 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 113 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1521 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.923

Publications

14 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=0.0042936504).

BP6

Variant 3-191369951-A-T is Benign according to our data. Variant chr3-191369951-A-T is described in ClinVar as Benign. ClinVar VariationId is 48154.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 = 0.0325 (4948/152336) while in subpopulation NFE AF = 0.0465 (3165/68028). AF 95% confidence interval is 0.0452. There are 113 homozygotes in GnomAd4. There are 2390 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4948 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3 link	c.363A>T	p.Leu121Phe	missense_variant	Exon 5 of 12	ENST00000392455.9	NP_848018.1	Q8IVM0-2
CCDC50	NM_174908.4 link	c.363A>T	p.Leu121Phe	missense_variant	Exon 5 of 11		NP_777568.1	Q8IVM0-1
CCDC50	XM_011512460.2 link	c.363A>T	p.Leu121Phe	missense_variant	Exon 5 of 8		XP_011510762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC50	ENST00000392455.9 link	c.363A>T	p.Leu121Phe	missense_variant	Exon 5 of 12	1	NM_178335.3	ENSP00000376249.4	Q8IVM0-2
CCDC50	ENST00000392456.4 link	c.363A>T	p.Leu121Phe	missense_variant	Exon 5 of 11	1		ENSP00000376250.4	Q8IVM0-1
CCDC50	ENST00000460064.1 link	n.90A>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4951

AN:

152218

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0106

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0456

Gnomad FIN

AF:

0.0414

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0359

GnomAD2 exomes

AF:

0.0353

AC:

8851

AN:

251070

AF XY:

0.0372

show subpopulations

Gnomad AFR exome

AF:

0.00929

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0334

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0395

Gnomad NFE exome

AF:

0.0462

Gnomad OTH exome

AF:

0.0410

GnomAD4 exome

AF:

0.0434

AC:

63343

AN:

1460540

Hom.:

1521

Cov.:

AF XY:

0.0437

AC XY:

31718

AN XY:

726604

show subpopulations

African (AFR)

AF:

0.00921

AC:

308

AN:

33434

American (AMR)

AF:

0.0193

AC:

861

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

915

AN:

26100

East Asian (EAS)

AF:

0.000328

AC:

AN:

39666

South Asian (SAS)

AF:

0.0445

AC:

3835

AN:

86232

European-Finnish (FIN)

AF:

0.0412

AC:

2198

AN:

53306

Middle Eastern (MID)

AF:

0.0540

AC:

311

AN:

5764

European-Non Finnish (NFE)

AF:

0.0470

AC:

52251

AN:

1111008

Other (OTH)

AF:

0.0439

AC:

2651

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

2918

5836

8754

11672

14590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1930

3860

5790

7720

9650

<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:

0.0325

AC:

4948

AN:

152336

Hom.:

113

Cov.:

AF XY:

0.0321

AC XY:

2390

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0106

AC:

440

AN:

41588

American (AMR)

AF:

0.0305

AC:

466

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

122

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.0454

AC:

219

AN:

4824

European-Finnish (FIN)

AF:

0.0414

AC:

440

AN:

10626

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0465

AC:

3165

AN:

68028

Other (OTH)

AF:

0.0355

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

247

495

742

990

1237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0428

Hom.:

127

Bravo

AF:

0.0297

TwinsUK

AF:

0.0539

AC:

200

ALSPAC

AF:

0.0472

AC:

182

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0508

AC:

437

ExAC

AF:

0.0364

AC:

4424

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0462

EpiControl

AF:

0.0430

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu121Phe in Exon 05 of CCDC50: This variant is not expected to have clinical si gnificance because it has been identified in 5.3% (370/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs35380043). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 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 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 12, 2018

Athena Diagnostics

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

- -

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

0.26

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

.;T

Eigen

Benign

0.045

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

0.92

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.13

Sift

Benign

0.062

T;D

Sift4G

Benign

0.33

T;T

Polyphen

1.0

D;D

Vest4

0.32

MutPred

0.091

Gain of methylation at K119 (P = 0.0876);Gain of methylation at K119 (P = 0.0876);

MPC

0.71

ClinPred

0.016

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.047

gMVP

0.091

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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