NM_178335.3:c.1231C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_178335.3(CCDC50):c.1231C>T(p.Pro411Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P411T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.239

Publications

1 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029593527).

BP6

Variant 3-191380921-C-T is Benign according to our data. Variant chr3-191380921-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178292.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3 link	c.1231C>T	p.Pro411Ser	missense_variant	Exon 9 of 12	ENST00000392455.9	NP_848018.1	Q8IVM0-2
CCDC50	NM_174908.4 link	c.703C>T	p.Pro235Ser	missense_variant	Exon 8 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.1231C>T	p.Pro411Ser	missense_variant	Exon 9 of 12	1	NM_178335.3	ENSP00000376249.4		Q8IVM0-2
CCDC50	ENST00000392456.4 link	c.703C>T	p.Pro235Ser	missense_variant	Exon 8 of 11	1		ENSP00000376250.4		Q8IVM0-1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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

GnomAD2 exomes

AF:

0.00

AC:

AN:

248600

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459754

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33392

American (AMR)

AF:

0.00

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39592

South Asian (SAS)

AF:

0.00

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110622

Other (OTH)

AF:

0.00

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000198

AC:

AN:

151866

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41338

American (AMR)

AF:

0.0000657

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000659

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Oct 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1231C>T (p.P411S) alteration is located in exon 9 (coding exon 9) of the CCDC50 gene. This alteration results from a C to T substitution at nucleotide position 1231, causing the proline (P) at amino acid position 411 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Aug 07, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro411Ser in exon 9 of CCDC50: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, squirrel, dog, and star-nosed mole have a serine (Ser) at this position. In addition, computational prediction tools do not suggest a high likelihood of imp act to the protein. This variant has also been identified in 1/8598 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washin gton.edu/EVS/; dbSNP rs138707536). -

not provided

Uncertain:1

Jan 10, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

2.5

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0070

.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

.;L

PhyloP100

-0.24

PrimateAI

Benign

0.27

REVEL

Benign

0.075

Polyphen

0.0090

B;B

MVP

0.15

MPC

0.17

ClinPred

0.063

GERP RS

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.064

gMVP

0.025

Mutation Taster

=88/12

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