NM_178335.3:c.50-69delA

Variant names:

• chr3-191357007-TA-T
• rs879004278
• NM_178335.3:c.50-69delA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_178335.3(CCDC50):​c.50-69delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 556,316 control chromosomes in the GnomAD database, including 3 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.26 (1 hom.)
• Consequence: CCDC50 NM_178335.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 366 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.50-69delA		intron	N/A	NP_848018.1	Q8IVM0-2
	CCDC50	NM_174908.4		c.50-69delA		intron	N/A	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.50-80delA		intron	N/A	ENSP00000376249.4	Q8IVM0-2
	CCDC50	ENST00000392456.4	TSL:1	c.50-80delA		intron	N/A	ENSP00000376250.4	Q8IVM0-1
	CCDC50	ENST00000899243.1		c.50-80delA		intron	N/A	ENSP00000569302.1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 364 AN: 145410 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00412

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00398

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.000789

Gnomad SAS AF: 0.00174

Gnomad FIN AF: 0.00391

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00136

Gnomad OTH AF: 0.000508

GnomAD4 exome AF: 0.260 AC: 106764 AN: 410842 Hom.: 1 AF XY: 0.266 AC XY: 57152 AN XY: 215130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.226 AC: 2373 AN: 10514

American (AMR) AF: 0.266 AC: 5724 AN: 21520

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 3439 AN: 10872

East Asian (EAS) AF: 0.325 AC: 5276 AN: 16220

South Asian (SAS) AF: 0.311 AC: 9822 AN: 31616

European-Finnish (FIN) AF: 0.258 AC: 6833 AN: 26442

Middle Eastern (MID) AF: 0.146 AC: 427 AN: 2930

European-Non Finnish (NFE) AF: 0.249 AC: 67436 AN: 271220

Other (OTH) AF: 0.279 AC: 5434 AN: 19508

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00252 AC: 366 AN: 145474 Hom.: 2 Cov.: 32 AF XY: 0.00291 AC XY: 206 AN XY: 70708

African (AFR) AF: 0.00416 AC: 167 AN: 40112

American (AMR) AF: 0.00397 AC: 58 AN: 14604

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 4 AN: 3382

East Asian (EAS) AF: 0.000791 AC: 4 AN: 5058

South Asian (SAS) AF: 0.00174 AC: 8 AN: 4586

European-Finnish (FIN) AF: 0.00391 AC: 35 AN: 8944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00136 AC: 89 AN: 65620

Other (OTH) AF: 0.000503 AC: 1 AN: 1990

Alfa AF: 0.000387 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

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: rs879004278; hg19: chr3-191074796; COSMIC: COSV66667597; COSMIC: COSV66667597;