3-191375595-A-G

Position:

• chr3-191375595-A-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.976+6A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,610,156 control chromosomes in the GnomAD database, including 137,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18886 hom., cov: 30)
  • Exomes 𝑓: 0.40 (118884 hom.)
• Consequence: CCDC50 NM_178335.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001828
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.280

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=-0.83).
• BP6: Variant 3-191375595-A-G is Benign according to our data. Variant chr3-191375595-A-G is described in ClinVar as [Benign]. Clinvar id is 48160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-191375595-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.976+6A>G		splice_donor_region_variant, intron_variant		ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.449-4564A>G		intron_variant			NP_777568.1
CCDC50	XM_011512460.2	c.976+6A>G		splice_donor_region_variant, intron_variant			XP_011510762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.976+6A>G		splice_donor_region_variant, intron_variant		1	NM_178335.3	ENSP00000376249	P3
CCDC50	ENST00000392456.4	c.449-4564A>G		intron_variant		1		ENSP00000376250	A1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73225 AN: 151700 Hom.: 18860 Cov.: 30

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.459

GnomAD3 exomes AF: 0.425 AC: 104123 AN: 245184 Hom.: 22685 AF XY: 0.413 AC XY: 54897 AN XY: 132972

Gnomad AFR exome AF: 0.681

Gnomad AMR exome AF: 0.494

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.452

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.400 AC: 583884 AN: 1458336 Hom.: 118884 Cov.: 39 AF XY: 0.397 AC XY: 288197 AN XY: 725310

Gnomad4 AFR exome AF: 0.684

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.459

Gnomad4 EAS exome AF: 0.410

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.368

Gnomad4 NFE exome AF: 0.391

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.483 AC: 73311 AN: 151820 Hom.: 18886 Cov.: 30 AF XY: 0.481 AC XY: 35682 AN XY: 74170

Gnomad4 AFR AF: 0.683

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.453

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.458

Alfa AF: 0.426 Hom.: 4934

Bravo AF: 0.503

Asia WGS AF: 0.440 AC: 1528 AN: 3478

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	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	976+6A>G in Intron 06 of CCDC50: This variant is not expected to have clinical s ignificance because it has been identified in 38.9% (2708/6964) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs4677729). -

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_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.012
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: rs4677729; hg19: chr3-191093384; COSMIC: COSV66668397;