NM_178335.3:c.363A>T

Variant names:

• chr3-191369951-A-T
• rs35380043
• NM_178335.3:c.363A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (113 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1521 hom.)
• Consequence: CCDC50 NM_178335.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.923
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss 44

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4948 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178335.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	NM_178335.3	MANE Select	c.363A>T	p.Leu121Phe	missense	Exon 5 of 12	NP_848018.1	Q8IVM0-2
	CCDC50	NM_174908.4		c.363A>T	p.Leu121Phe	missense	Exon 5 of 11	NP_777568.1	Q8IVM0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	ENST00000392455.9	TSL:1 MANE Select	c.363A>T	p.Leu121Phe	missense	Exon 5 of 12	ENSP00000376249.4	Q8IVM0-2
	CCDC50	ENST00000392456.4	TSL:1	c.363A>T	p.Leu121Phe	missense	Exon 5 of 11	ENSP00000376250.4	Q8IVM0-1
	CCDC50	ENST00000899243.1		c.363A>T	p.Leu121Phe	missense	Exon 5 of 13	ENSP00000569302.1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4951 AN: 152218 Hom.: 113 Cov.: 32

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

GnomAD2 exomes AF: 0.0353 AC: 8851 AN: 251070 AF XY: 0.0372

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 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.: 30 AF XY: 0.0437 AC XY: 31718 AN XY: 726604

African (AFR) AF: 0.00921 AC: 308 AN: 33434

American (AMR) AF: 0.0193 AC: 861 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 915 AN: 26100

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39666

South Asian (SAS) AF: 0.0445 AC: 3835 AN: 86232

European-Finnish (FIN) AF: 0.0412 AC: 2198 AN: 53306

Middle Eastern (MID) AF: 0.0540 AC: 311 AN: 5764

European-Non Finnish (NFE) AF: 0.0470 AC: 52251 AN: 1111008

Other (OTH) AF: 0.0439 AC: 2651 AN: 60328

GnomAD4 genome AF: 0.0325 AC: 4948 AN: 152336 Hom.: 113 Cov.: 32 AF XY: 0.0321 AC XY: 2390 AN XY: 74496

African (AFR) AF: 0.0106 AC: 440 AN: 41588

American (AMR) AF: 0.0305 AC: 466 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0454 AC: 219 AN: 4824

European-Finnish (FIN) AF: 0.0414 AC: 440 AN: 10626

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0465 AC: 3165 AN: 68028

Other (OTH) AF: 0.0355 AC: 75 AN: 2114

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: 51

ESP6500EA AF: 0.0508 AC: 437

ExAC AF: 0.0364 AC: 4424

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0462

EpiControl AF: 0.0430

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Nonsyndromic genetic hearing loss (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T
Eigen	Benign	0.045
Eigen_PC	Benign	-0.049
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.92
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Benign	0.062	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.32
MutPred		0.091		Gain of methylation at K119 (P = 0.0876)
MPC		0.71
ClinPred		0.016	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.091
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35380043; hg19: chr3-191087740; COSMIC: COSV66668390;