rs146511344

Positions:

• chr3-191380893-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_178335.3(CCDC50):​c.1203A>G​(p.Lys401Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,612,942 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: CCDC50 NM_178335.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.455

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-191380893-A-G is Benign according to our data. Variant chr3-191380893-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 162861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-191380893-A-G is described in Lovd as [Likely_benign]. Variant chr3-191380893-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.455 with no splicing effect.
• BS2: High AC in GnomAd4 at 239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.1203A>G	p.Lys401Lys	synonymous_variant	9/12	ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.675A>G	p.Lys225Lys	synonymous_variant	8/11		NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.1203A>G	p.Lys401Lys	synonymous_variant	9/12	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.675A>G	p.Lys225Lys	synonymous_variant	8/11	1		ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00171 AC: 427 AN: 250150 Hom.: 0 AF XY: 0.00180 AC XY: 244 AN XY: 135242

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.000959

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000602

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00225 AC: 3286 AN: 1460694 Hom.: 7 Cov.: 33 AF XY: 0.00218 AC XY: 1587 AN XY: 726640

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.000581

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74444

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00155

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00238

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CCDC50: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Lys401Lys in Exon 09 of CCDC50: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.3% (21/7018) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs146511344). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2017	- -

CCDC50-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.3
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Other links and lift over

dbSNP: rs146511344; hg19: chr3-191098682;