rs143628723

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2

The NM_178335.3(CCDC50):c.1144G>A(p.Ala382Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000184 in 1,612,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 6.08

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 5: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann [when max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.013216823).

BP6

Variant 3-191380834-G-A is Benign according to our data. Variant chr3-191380834-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162859.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC50	NM_178335.3 linkuse as main transcript	c.1144G>A	p.Ala382Thr	missense_variant	9/12	ENST00000392455.9
CCDC50	NM_174908.4 linkuse as main transcript	c.616G>A	p.Ala206Thr	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC50	ENST00000392455.9 linkuse as main transcript	c.1144G>A	p.Ala382Thr	missense_variant	9/12	1	NM_178335.3	P3	Q8IVM0-2
CCDC50	ENST00000392456.4 linkuse as main transcript	c.616G>A	p.Ala206Thr	missense_variant	8/11	1		A1	Q8IVM0-1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000412

AC:

103

AN:

250238

Hom.:

AF XY:

0.000429

AC XY:

AN XY:

135310

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00855

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1460634

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00744

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.000597

GnomAD4 genome

AF:

0.000224

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000452

Hom.:

Bravo

AF:

0.000208

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 31, 2017	The p.Ala382Thr variant (rs143628723) has not been previously associated with hearing loss, and is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 162859). However, this variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.86% (identified in 87 out of 10,130 chromosomes). While the alanine at codon 382 is highly conserved (Alamut software v 2.8.1), due to similar physiochemical properties between alanine and the substituted threonine, computational analyses return mixed results regarding the effect of this variant on CCDC50 protein structure/function (SIFT: damaging, PolyPhen2: benign, and Mutation Taster: disease causing). This variant is not predicted to alter CCDC50mRNA splicing (Alamut software v 2.8.1). Pathogenic variants in CCDC50 are associated with an autosomal dominant form of hearing loss (MIM: 607453), and based on the ethnic specific population frequency of this variant, p.Ala382Thr is likely to be benign. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2013	Variant classified as Uncertain Significance - Favor Benign. The Ala382Thr varia nt in CCDC50 has not been reported in individuals with hearing loss, but has bee n identified in 0.05% (4/8458) of European American chromosomes in a broad popul ation by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs143628723). Although this variant has been seen in the general populati on, its frequency is not high enough to rule out a pathogenic role. Computationa l analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen 2, and SIFT) do not provide strong support for or against an impact to the prote in. In summary, the clinical significance of this variant cannot be determined w ith certainty; however, based upon the its presence in the general population, w e would lean towards a more likely benign role. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 12, 2022	The c.1144G>A (p.A382T) alteration is located in exon 9 (coding exon 9) of the CCDC50 gene. This alteration results from a G to A substitution at nucleotide position 1144, causing the alanine (A) at amino acid position 382 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.6

.;M

MutationTaster

Benign

0.80

D;D

PrimateAI

Uncertain

0.65

REVEL

Uncertain

0.53

Polyphen

0.87

P;D

MVP

0.85

MPC

0.61

ClinPred

0.27

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over