chr3-191369951-A-T

Position:

chr3-191369951-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_178335.3(CCDC50):c.363A>T(p.Leu121Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,612,876 control chromosomes in the GnomAD database, including 1,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.032 ( 113 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1521 hom. )

Consequence

CCDC50
NM_178335.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.923

Variant links:

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]

CCDC50 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042936504).

BP6

Variant 3-191369951-A-T is Benign according to our data. Variant chr3-191369951-A-T is described in ClinVar as [Benign]. Clinvar id is 48154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0325 (4948/152336) while in subpopulation NFE AF= 0.0465 (3165/68028). AF 95% confidence interval is 0.0452. There are 113 homozygotes in gnomad4. There are 2390 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4948 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC50	NM_178335.3 link	c.363A>T	p.Leu121Phe	missense_variant	5/12	ENST00000392455.9	NP_848018.1	Q8IVM0-2
CCDC50	NM_174908.4 link	c.363A>T	p.Leu121Phe	missense_variant	5/11		NP_777568.1	Q8IVM0-1
CCDC50	XM_011512460.2 link	c.363A>T	p.Leu121Phe	missense_variant	5/8		XP_011510762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CCDC50	ENST00000392455.9 link	c.363A>T	p.Leu121Phe	missense_variant	5/12	1	NM_178335.3	ENSP00000376249.4	Q8IVM0-2
CCDC50	ENST00000392456.4 link	c.363A>T	p.Leu121Phe	missense_variant	5/11	1		ENSP00000376250.4	Q8IVM0-1
CCDC50	ENST00000460064.1 link	n.90A>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4951

AN:

152218

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0106

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0305

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0456

Gnomad FIN

AF:

0.0414

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0465

Gnomad OTH

AF:

0.0359

GnomAD3 exomes

AF:

0.0353

AC:

8851

AN:

251070

Hom.:

206

AF XY:

0.0372

AC XY:

5049

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.00929

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0334

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0449

Gnomad FIN exome

AF:

0.0395

Gnomad NFE exome

AF:

0.0462

Gnomad OTH exome

AF:

0.0410

GnomAD4 exome

AF:

0.0434

AC:

63343

AN:

1460540

Hom.:

1521

Cov.:

AF XY:

0.0437

AC XY:

31718

AN XY:

726604

show subpopulations

Gnomad4 AFR exome

AF:

0.00921

Gnomad4 AMR exome

AF:

0.0193

Gnomad4 ASJ exome

AF:

0.0351

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0445

Gnomad4 FIN exome

AF:

0.0412

Gnomad4 NFE exome

AF:

0.0470

Gnomad4 OTH exome

AF:

0.0439

GnomAD4 genome

AF:

0.0325

AC:

4948

AN:

152336

Hom.:

113

Cov.:

AF XY:

0.0321

AC XY:

2390

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0106

Gnomad4 AMR

AF:

0.0305

Gnomad4 ASJ

AF:

0.0351

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0454

Gnomad4 FIN

AF:

0.0414

Gnomad4 NFE

AF:

0.0465

Gnomad4 OTH

AF:

0.0355

Alfa

AF:

0.0428

Hom.:

127

Bravo

AF:

0.0297

TwinsUK

AF:

0.0539

AC:

200

ALSPAC

AF:

0.0472

AC:

182

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0508

AC:

437

ExAC

AF:

0.0364

AC:

4424

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0462

EpiControl

AF:

0.0430

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Leu121Phe in Exon 05 of CCDC50: This variant is not expected to have clinical si gnificance because it has been identified in 5.3% (370/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs35380043). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

.;T

Eigen

Benign

0.045

Eigen_PC

Benign

-0.049

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.13

Sift

Benign

0.062

T;D

Sift4G

Benign

0.33

T;T

Polyphen

1.0

D;D

Vest4

0.32

MutPred

0.091

Gain of methylation at K119 (P = 0.0876);Gain of methylation at K119 (P = 0.0876);

MPC

0.71

ClinPred

0.016

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.047

gMVP

0.091

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over