rs114502673

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.1181A>G(p.Lys394Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,613,084 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 89 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.09

Publications

12 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=0.006295413).

BP6

Variant 3-191380871-A-G is Benign according to our data. Variant chr3-191380871-A-G is described in ClinVar as Benign. ClinVar VariationId is 162860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00385 (586/152226) while in subpopulation SAS AF = 0.023 (111/4830). AF 95% confidence interval is 0.0195. There are 4 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 586 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3 link	c.1181A>G	p.Lys394Arg	missense_variant	Exon 9 of 12	ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4 link	c.653A>G	p.Lys218Arg	missense_variant	Exon 8 of 11		NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9 link	c.1181A>G	p.Lys394Arg	missense_variant	Exon 9 of 12	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4 link	c.653A>G	p.Lys218Arg	missense_variant	Exon 8 of 11	1		ENSP00000376250.4

Frequencies

GnomAD3 genomes

AF:

0.00383

AC:

583

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0225

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00556

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00605

AC:

1515

AN:

250402

AF XY:

0.00724

show subpopulations

Gnomad AFR exome

AF:

0.000929

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00437

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00549

Gnomad OTH exome

AF:

0.00624

GnomAD4 exome

AF:

0.00648

AC:

9468

AN:

1460858

Hom.:

Cov.:

AF XY:

0.00727

AC XY:

5284

AN XY:

726724

show subpopulations

African (AFR)

AF:

0.000748

AC:

AN:

33434

American (AMR)

AF:

0.00157

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00575

AC:

150

AN:

26084

East Asian (EAS)

AF:

0.000126

AC:

AN:

39652

South Asian (SAS)

AF:

0.0258

AC:

2221

AN:

86224

European-Finnish (FIN)

AF:

0.000449

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00586

AC:

6517

AN:

1111326

Other (OTH)

AF:

0.00654

AC:

395

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

504

1008

1511

2015

2519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.00385

AC:

586

AN:

152226

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

276

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

41562

American (AMR)

AF:

0.00177

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0230

AC:

111

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00556

AC:

378

AN:

67978

Other (OTH)

AF:

0.00380

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00365

Hom.:

Bravo

AF:

0.00344

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00639

AC:

776

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.00627

EpiControl

AF:

0.00599

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 11, 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. -

Sep 07, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lys394Arg in Exon 09 of CCDC50: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (30/7018) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs114502673). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 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

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0047

.;T

Eigen

Benign

0.090

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.80

T;T

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

3.1

PrimateAI

Uncertain

0.61

REVEL

Benign

0.092

Polyphen

0.70

P;B

MVP

0.39

MPC

0.46

ClinPred

0.019

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.019

Mutation Taster

=91/9

polymorphism

(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