rs138153104

Positions:

• chr3-191375230-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_178335.3(CCDC50):​c.617C>T​(p.Ser206Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,613,812 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: CCDC50 NM_178335.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 3.81

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017400056).
• BP6: Variant 3-191375230-C-T is Benign according to our data. Variant chr3-191375230-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228479.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=3}. Variant chr3-191375230-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.617C>T	p.Ser206Phe	missense_variant	6/12	ENST00000392455.9	NP_848018.1
CCDC50	XM_011512460.2	c.617C>T	p.Ser206Phe	missense_variant	6/8		XP_011510762.1
CCDC50	NM_174908.4	c.449-4929C>T		intron_variant			NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.617C>T	p.Ser206Phe	missense_variant	6/12	1	NM_178335.3	ENSP00000376249	P3
CCDC50	ENST00000392456.4	c.449-4929C>T		intron_variant		1		ENSP00000376250	A1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000699 AC: 175 AN: 250516 Hom.: 0 AF XY: 0.000731 AC XY: 99 AN XY: 135366

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00125 AC: 1834 AN: 1461556 Hom.: 3 Cov.: 31 AF XY: 0.00125 AC XY: 908 AN XY: 727070

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74444

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.000824

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.00158

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2018	Variant classified as Uncertain Significance - Favor Benign. The p.Ser206Phe var iant in CCDC50 has been previously identified by our laboratory in two individua ls with hearing loss, one of whom had an alternate genetic etiology for their he aring loss (LMM data). This variant has also been identified in 0.12% (154/12597 2) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs138153104). Although this variant has been seen in the general population, its frequency is not high enough to rule out a patho genic role. Computational prediction tools and conservation analysis suggest tha t the p.Ser206Phe variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ser206Phe variant is uncertain, these data suggest that i t is more likely to be benign. ACMG/AMP Criteria applied: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2022	The c.617C>T (p.S206F) alteration is located in exon 6 (coding exon 6) of the CCDC50 gene. This alteration results from a C to T substitution at nucleotide position 617, causing the serine (S) at amino acid position 206 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CCDC50: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 206 of the CCDC50 protein (p.Ser206Phe). This variant is present in population databases (rs138153104, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CCDC50-related conditions. ClinVar contains an entry for this variant (Variation ID: 228479). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CCDC50-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.046
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
Polyphen		1.0	D
ClinPred		0.55	D
GERP RS		5.8
gMVP		0.10

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: rs138153104; hg19: chr3-191093019;