3-191380177-T-C

Variant names:

• chr3-191380177-T-C
• rs293813
• NM_178335.3:c.995T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178335.3(CCDC50):​c.995T>C​(p.Met332Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 1,587,576 control chromosomes in the GnomAD database, including 195,866 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26808 hom., cov: 28)
  • Exomes 𝑓: 0.48 (169058 hom.)
• Consequence: CCDC50 NM_178335.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.395
• Publications: 46 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.579161E-7).
• BP6: Variant 3-191380177-T-C is Benign according to our data. Variant chr3-191380177-T-C is described in ClinVar as Benign. ClinVar VariationId is 48161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 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.995T>C	p.Met332Thr	missense	Exon 7 of 12	NP_848018.1
	CCDC50	NM_174908.4		c.467T>C	p.Met156Thr	missense	Exon 6 of 11	NP_777568.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	ENST00000392455.9	TSL:1 MANE Select	c.995T>C	p.Met332Thr	missense	Exon 7 of 12	ENSP00000376249.4
	CCDC50	ENST00000392456.4	TSL:1	c.467T>C	p.Met156Thr	missense	Exon 6 of 11	ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.577 AC: 86892 AN: 150574 Hom.: 26756 Cov.: 28

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.533 AC: 132416 AN: 248634 AF XY: 0.520

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.626

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.682

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.465

Gnomad OTH exome AF: 0.507

GnomAD4 exome AF: 0.478 AC: 687415 AN: 1436890 Hom.: 169058 Cov.: 29 AF XY: 0.478 AC XY: 342157 AN XY: 716052

African (AFR) AF: 0.813 AC: 26768 AN: 32906

American (AMR) AF: 0.619 AC: 27480 AN: 44416

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 13022 AN: 25876

East Asian (EAS) AF: 0.644 AC: 25440 AN: 39474

South Asian (SAS) AF: 0.516 AC: 43957 AN: 85186

European-Finnish (FIN) AF: 0.444 AC: 23679 AN: 53314

Middle Eastern (MID) AF: 0.466 AC: 2657 AN: 5706

European-Non Finnish (NFE) AF: 0.454 AC: 494855 AN: 1090578

Other (OTH) AF: 0.497 AC: 29557 AN: 59434

GnomAD4 genome AF: 0.577 AC: 86996 AN: 150686 Hom.: 26808 Cov.: 28 AF XY: 0.577 AC XY: 42426 AN XY: 73472

African (AFR) AF: 0.806 AC: 33181 AN: 41158

American (AMR) AF: 0.566 AC: 8530 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.503 AC: 1739 AN: 3454

East Asian (EAS) AF: 0.667 AC: 3408 AN: 5110

South Asian (SAS) AF: 0.522 AC: 2494 AN: 4776

European-Finnish (FIN) AF: 0.440 AC: 4446 AN: 10098

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31582 AN: 67718

Other (OTH) AF: 0.543 AC: 1137 AN: 2094

Alfa AF: 0.515 Hom.: 69559

Bravo AF: 0.599

TwinsUK AF: 0.447 AC: 1659

ALSPAC AF: 0.462 AC: 1780

ESP6500AA AF: 0.790 AC: 3482

ESP6500EA AF: 0.461 AC: 3965

ExAC AF: 0.533 AC: 64629

Asia WGS AF: 0.624 AC: 2167 AN: 3476

EpiCase AF: 0.464

EpiControl AF: 0.466

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

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

Met332Thr in Exon 07 of CCDC50: This variant is not expected to have clinical si gnificance because it has been identified in 46.1% (3235/7020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs293813).

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.069
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.7
DANN	Benign	0.23
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N
PhyloP100		0.40
PrimateAI	Benign	0.27	T
REVEL	Benign	0.015
Polyphen		0.0	B
MPC		0.19
ClinPred		0.0093	T
GERP RS		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.031
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs293813; hg19: chr3-191097966; COSMIC: COSV66667473;