rs188384

chr3-191357084-C-G

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.50-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,596,420 control chromosomes in the GnomAD database, including 256,916 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (34148 hom., cov: 31)
  • Exomes 𝑓: 0.54 (222768 hom.)
• Consequence: CCDC50 NM_178335.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00008616
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.666

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=-0.79).
• BP6: Variant 3-191357084-C-G is Benign according to our data. Variant chr3-191357084-C-G is described in ClinVar as [Benign]. Clinvar id is 48155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-191357084-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC50	NM_178335.3	c.50-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000392455.9
CCDC50	NM_174908.4	c.50-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CCDC50	XM_011512460.2	c.50-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC50	ENST00000392455.9	c.50-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_178335.3	P3
CCDC50	ENST00000392456.4	c.50-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98902 AN: 151914 Hom.: 34096 Cov.: 31

Gnomad AFR AF: 0.863

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.605

GnomAD3 exomes AF: 0.628 AC: 157546 AN: 250812 Hom.: 52148 AF XY: 0.616 AC XY: 83504 AN XY: 135530

Gnomad AFR exome AF: 0.869

Gnomad AMR exome AF: 0.755

Gnomad ASJ exome AF: 0.551

Gnomad EAS exome AF: 0.932

Gnomad SAS exome AF: 0.681

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.545 AC: 786813 AN: 1444388 Hom.: 222768 Cov.: 32 AF XY: 0.547 AC XY: 393710 AN XY: 719742

Gnomad4 AFR exome AF: 0.871

Gnomad4 AMR exome AF: 0.748

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.898

Gnomad4 SAS exome AF: 0.680

Gnomad4 FIN exome AF: 0.553

Gnomad4 NFE exome AF: 0.502

Gnomad4 OTH exome AF: 0.568

GnomAD4 genome AF: 0.651 AC: 99011 AN: 152032 Hom.: 34148 Cov.: 31 AF XY: 0.659 AC XY: 48939 AN XY: 74288

Gnomad4 AFR AF: 0.863

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.919

Gnomad4 SAS AF: 0.694

Gnomad4 FIN AF: 0.566

Gnomad4 NFE AF: 0.516

Gnomad4 OTH AF: 0.604

Alfa AF: 0.551 Hom.: 7798

Bravo AF: 0.670

Asia WGS AF: 0.803 AC: 2786 AN: 3476

EpiCase AF: 0.512

EpiControl AF: 0.509

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	50-4C>G in Intron 01 of CCDC50: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce and has been identified in 49.3% (3462/7020) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs188384). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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	-0.79
Cadd	Benign	1.1
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.032
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: rs188384; hg19: chr3-191074873; COSMIC: COSV66669473; COSMIC: COSV66669473;