rs2028573

Variant names:

• chr3-191375291-A-G
• rs2028573
• NM_178335.3:c.678A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_178335.3(CCDC50):​c.678A>G​(p.Lys226Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,613,458 control chromosomes in the GnomAD database, including 12,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4038 hom., cov: 32)
  • Exomes 𝑓: 0.090 (8790 hom.)
• Consequence: CCDC50 NM_178335.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.614
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-191375291-A-G is Benign according to our data. Variant chr3-191375291-A-G is described in ClinVar as Benign. ClinVar VariationId is 48157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.614 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.678A>G	p.Lys226Lys	synonymous_variant	Exon 6 of 12	ENST00000392455.9	NP_848018.1
CCDC50	XM_011512460.2	c.678A>G	p.Lys226Lys	synonymous_variant	Exon 6 of 8		XP_011510762.1
CCDC50	NM_174908.4	c.449-4868A>G		intron_variant	Intron 5 of 10		NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.678A>G	p.Lys226Lys	synonymous_variant	Exon 6 of 12	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.449-4868A>G		intron_variant	Intron 5 of 10	1		ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27071 AN: 152014 Hom.: 4033 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.0930

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0727

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.123 AC: 30769 AN: 249834 AF XY: 0.114

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.0958

Gnomad EAS exome AF: 0.209

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0733

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0898 AC: 131291 AN: 1461326 Hom.: 8790 Cov.: 58 AF XY: 0.0889 AC XY: 64594 AN XY: 726970

African (AFR) AF: 0.416 AC: 13915 AN: 33440

American (AMR) AF: 0.170 AC: 7594 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0941 AC: 2458 AN: 26118

East Asian (EAS) AF: 0.212 AC: 8420 AN: 39662

South Asian (SAS) AF: 0.118 AC: 10141 AN: 86238

European-Finnish (FIN) AF: 0.0430 AC: 2296 AN: 53370

Middle Eastern (MID) AF: 0.148 AC: 851 AN: 5760

European-Non Finnish (NFE) AF: 0.0711 AC: 79058 AN: 1111722

Other (OTH) AF: 0.109 AC: 6558 AN: 60368

GnomAD4 genome AF: 0.178 AC: 27097 AN: 152132 Hom.: 4038 Cov.: 32 AF XY: 0.174 AC XY: 12974 AN XY: 74382

African (AFR) AF: 0.407 AC: 16877 AN: 41462

American (AMR) AF: 0.160 AC: 2451 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0930 AC: 323 AN: 3472

East Asian (EAS) AF: 0.213 AC: 1101 AN: 5174

South Asian (SAS) AF: 0.124 AC: 597 AN: 4826

European-Finnish (FIN) AF: 0.0393 AC: 417 AN: 10614

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.0726 AC: 4938 AN: 67982

Other (OTH) AF: 0.146 AC: 309 AN: 2114

Alfa AF: 0.107 Hom.: 3146

Bravo AF: 0.196

Asia WGS AF: 0.163 AC: 567 AN: 3478

EpiCase AF: 0.0763

EpiControl AF: 0.0768

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

Lys226Lys in Exon 06 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 39.2% (1467/3738) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2028573). -

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

Feb 02, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.38
DANN	Benign	0.36
PhyloP100		-0.61
Mutation Taster		=100/0	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: rs2028573; hg19: chr3-191093080; COSMIC: COSV66668040;