rs4677728

Positions:

• chr3-191375521-A-G
• chr3-191375521-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178335.3(CCDC50):​c.908A>G​(p.Lys303Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,612,776 control chromosomes in the GnomAD database, including 138,202 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18914 hom., cov: 30)
  • Exomes 𝑓: 0.40 (119288 hom.)
• Consequence: CCDC50 NM_178335.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.36

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.6898535E-6).
• BP6: Variant 3-191375521-A-G is Benign according to our data. Variant chr3-191375521-A-G is described in ClinVar as [Benign]. Clinvar id is 48159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-191375521-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.676 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.908A>G	p.Lys303Arg	missense_variant	6/12	ENST00000392455.9	NP_848018.1
CCDC50	XM_011512460.2	c.908A>G	p.Lys303Arg	missense_variant	6/8		XP_011510762.1
CCDC50	NM_174908.4	c.449-4638A>G		intron_variant			NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.908A>G	p.Lys303Arg	missense_variant	6/12	1	NM_178335.3	ENSP00000376249	P3
CCDC50	ENST00000392456.4	c.449-4638A>G		intron_variant		1		ENSP00000376250	A1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73274 AN: 151674 Hom.: 18888 Cov.: 30

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.460

GnomAD3 exomes AF: 0.427 AC: 106550 AN: 249270 Hom.: 23495 AF XY: 0.415 AC XY: 55994 AN XY: 134854

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.454

Gnomad SAS exome AF: 0.353

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.394

Gnomad OTH exome AF: 0.416

GnomAD4 exome AF: 0.401 AC: 585360 AN: 1460984 Hom.: 119288 Cov.: 50 AF XY: 0.398 AC XY: 289003 AN XY: 726788

Gnomad4 AFR exome AF: 0.684

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.410

Gnomad4 SAS exome AF: 0.360

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.483 AC: 73360 AN: 151792 Hom.: 18914 Cov.: 30 AF XY: 0.482 AC XY: 35735 AN XY: 74188

Gnomad4 AFR AF: 0.683

Gnomad4 AMR AF: 0.473

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.455

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.459

Alfa AF: 0.416 Hom.: 33001

Bravo AF: 0.503

TwinsUK AF: 0.384 AC: 1425

ALSPAC AF: 0.398 AC: 1532

ESP6500AA AF: 0.671 AC: 2953

ESP6500EA AF: 0.395 AC: 3398

ExAC AF: 0.427 AC: 51792

Asia WGS AF: 0.440 AC: 1528 AN: 3478

EpiCase AF: 0.395

EpiControl AF: 0.392

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Lys303Arg in Exon 06 of CCDC50: This variant is not expected to have clinical si gnificance because it has been identified in 39.5% (2771/7020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs4677728). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant nonsyndromic hearing loss 44 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.87
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0000047	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
Polyphen		0.11	B
ClinPred		0.0019	T
GERP RS		2.3
gMVP		0.013

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: rs4677728; hg19: chr3-191093310; COSMIC: COSV66668262;