3-191375386-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_178335.3(CCDC50):c.773T>A(p.Ile258Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,613,192 control chromosomes in the GnomAD database, including 138,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18937 hom., cov: 31)

Exomes 𝑓: 0.40 ( 119314 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.428

Publications

38 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=2.1176315E-6).

BP6

Variant 3-191375386-T-A is Benign according to our data. Variant chr3-191375386-T-A is described in ClinVar as Benign. ClinVar VariationId is 48158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178335.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	NM_178335.3	MANE Select	c.773T>A	p.Ile258Asn	missense	Exon 6 of 12	NP_848018.1
	CCDC50	NM_174908.4		c.449-4773T>A		intron	N/A	NP_777568.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	ENST00000392455.9	TSL:1 MANE Select	c.773T>A	p.Ile258Asn	missense	Exon 6 of 12	ENSP00000376249.4
	CCDC50	ENST00000392456.4	TSL:1	c.449-4773T>A		intron	N/A	ENSP00000376250.4

Frequencies

GnomAD3 genomes

AF:

0.483

AC:

73376

AN:

151854

Hom.:

18910

Cov.:

show subpopulations

Gnomad AFR

AF:

0.683

Gnomad AMI

AF:

0.258

Gnomad AMR

AF:

0.473

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.456

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.374

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.397

Gnomad OTH

AF:

0.459

GnomAD2 exomes

AF:

0.428

AC:

106843

AN:

249772

AF XY:

0.416

show subpopulations

Gnomad AFR exome

AF:

0.683

Gnomad AMR exome

AF:

0.497

Gnomad ASJ exome

AF:

0.461

Gnomad EAS exome

AF:

0.454

Gnomad FIN exome

AF:

0.371

Gnomad NFE exome

AF:

0.395

Gnomad OTH exome

AF:

0.416

GnomAD4 exome

AF:

0.401

AC:

585516

AN:

1461218

Hom.:

119314

Cov.:

AF XY:

0.398

AC XY:

289076

AN XY:

726876

show subpopulations

African (AFR)

AF:

0.684

AC:

22881

AN:

33458

American (AMR)

AF:

0.496

AC:

22109

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

11994

AN:

26122

East Asian (EAS)

AF:

0.410

AC:

16274

AN:

39660

South Asian (SAS)

AF:

0.360

AC:

31002

AN:

86216

European-Finnish (FIN)

AF:

0.368

AC:

19662

AN:

53364

Middle Eastern (MID)

AF:

0.387

AC:

2233

AN:

5766

European-Non Finnish (NFE)

AF:

0.391

AC:

434364

AN:

1111664

Other (OTH)

AF:

0.414

AC:

24997

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

21278

42556

63834

85112

106390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13706

27412

41118

54824

68530

<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:

0.483

AC:

73464

AN:

151974

Hom.:

18937

Cov.:

AF XY:

0.482

AC XY:

35785

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.683

AC:

28327

AN:

41468

American (AMR)

AF:

0.473

AC:

7215

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

1599

AN:

3466

East Asian (EAS)

AF:

0.455

AC:

2350

AN:

5160

South Asian (SAS)

AF:

0.352

AC:

1697

AN:

4818

European-Finnish (FIN)

AF:

0.374

AC:

3952

AN:

10566

Middle Eastern (MID)

AF:

0.469

AC:

138

AN:

294

European-Non Finnish (NFE)

AF:

0.397

AC:

26983

AN:

67920

Other (OTH)

AF:

0.458

AC:

968

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1862

3724

5586

7448

9310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<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:

0.416

Hom.:

10216

Bravo

AF:

0.503

TwinsUK

AF:

0.385

AC:

1426

ALSPAC

AF:

0.398

AC:

1532

ESP6500AA

AF:

0.671

AC:

2955

ESP6500EA

AF:

0.396

AC:

3404

ExAC

AF:

0.427

AC:

51829

Asia WGS

AF:

0.440

AC:

1530

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

May 09, 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.

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ile258Asn in Exon 06 of CCDC50: This variant is not expected to have clinical si gnificance because it has been identified in 39.5% (2775/7020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2028574).

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Feb 03, 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

Autosomal dominant nonsyndromic hearing loss 44

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.85

(source)

DANN

Benign

0.24

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0000021

MetaSVM

Benign

-0.95

PhyloP100

-0.43

PrimateAI

Benign

0.22

Polyphen

0.0

ClinPred

0.0011

GERP RS

-3.5

gMVP

0.045

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over