chr3-191375230-C-T

Variant names:

• chr3-191375230-C-T
• rs138153104
• NM_178335.3:c.617C>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:2 B:5
• 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: {Likely_benign=1, Benign=3, Uncertain_significance=2}. 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 rank	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.617C>T	p.Ser206Phe	missense_variant	Exon 6 of 12	ENST00000392455.9	NP_848018.1
CCDC50	XM_011512460.2	c.617C>T	p.Ser206Phe	missense_variant	Exon 6 of 8		XP_011510762.1
CCDC50	NM_174908.4	c.449-4929C>T		intron_variant	Intron 5 of 10		NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.617C>T	p.Ser206Phe	missense_variant	Exon 6 of 12	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.449-4929C>T		intron_variant	Intron 5 of 10	1		ENSP00000376250.4

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:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Apr 14, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Benign:3

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCDC50: BP4, BS1, BS2 -

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CCDC50-related disorder Benign:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
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;