rs211043

Positions:

• chr3-191380942-G-A
• chr3-191380942-G-C

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.1242+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,601,236 control chromosomes in the GnomAD database, including 198,106 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27048 hom., cov: 32)
  • Exomes 𝑓: 0.48 (171058 hom.)
• Consequence: CCDC50 NM_178335.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.478

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 (BayesDel_noAF=-0.77).
• BP6: Variant 3-191380942-G-A is Benign according to our data. Variant chr3-191380942-G-A is described in ClinVar as [Benign]. Clinvar id is 48150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-191380942-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.1242+10G>A		intron_variant		ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.714+10G>A		intron_variant			NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.1242+10G>A		intron_variant		1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.714+10G>A		intron_variant		1		ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87672 AN: 151792 Hom.: 26994 Cov.: 32

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.546

GnomAD3 exomes AF: 0.534 AC: 127772 AN: 239112 Hom.: 35125 AF XY: 0.522 AC XY: 67586 AN XY: 129522

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.627

Gnomad ASJ exome AF: 0.506

Gnomad EAS exome AF: 0.684

Gnomad SAS exome AF: 0.518

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.508

GnomAD4 exome AF: 0.481 AC: 696616 AN: 1449326 Hom.: 171058 Cov.: 30 AF XY: 0.480 AC XY: 345885 AN XY: 720928

Gnomad4 AFR exome AF: 0.813

Gnomad4 AMR exome AF: 0.619

Gnomad4 ASJ exome AF: 0.504

Gnomad4 EAS exome AF: 0.645

Gnomad4 SAS exome AF: 0.518

Gnomad4 FIN exome AF: 0.444

Gnomad4 NFE exome AF: 0.457

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.578 AC: 87781 AN: 151910 Hom.: 27048 Cov.: 32 AF XY: 0.578 AC XY: 42880 AN XY: 74212

Gnomad4 AFR AF: 0.806

Gnomad4 AMR AF: 0.566

Gnomad4 ASJ AF: 0.505

Gnomad4 EAS AF: 0.665

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.544

Alfa AF: 0.540 Hom.: 6835

Bravo AF: 0.599

Asia WGS AF: 0.626 AC: 2171 AN: 3476

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	1242+10G>A in Intron 09 of CCDC50: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 46.1% (3234/7016) of European American chromos omes from a broad population by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS; dbSNP rs211043). -
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. -

not provided Benign:2

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

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_noAF	Benign	-0.77
CADD	Benign	9.8
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs211043; hg19: chr3-191098731; COSMIC: COSV66667470;