3-191356994-ATT-AT

Variant names:

• chr3-191356994-AT-A
• rs35377745
• NM_178335.3:c.50-86delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_178335.3(CCDC50):​c.50-86delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0816 in 791,716 control chromosomes in the GnomAD database, including 3,271 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.078 (531 hom., cov: 31)
  • Exomes 𝑓: 0.082 (2740 hom.)
• Consequence: CCDC50 NM_178335.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63
• 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 44

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 3-191356994-AT-A is Benign according to our data. Variant chr3-191356994-AT-A is described in ClinVar as [Benign]. Clinvar id is 1235084.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.50-86delT		intron_variant	Intron 1 of 11	ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.50-86delT		intron_variant	Intron 1 of 10		NP_777568.1
CCDC50	XM_011512460.2	c.50-86delT		intron_variant	Intron 1 of 7		XP_011510762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.50-93delT		intron_variant	Intron 1 of 11	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.50-93delT		intron_variant	Intron 1 of 10	1		ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.0781 AC: 11820 AN: 151324 Hom.: 528 Cov.: 31

Gnomad AFR AF: 0.0527

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0778

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.0609

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.0816

Gnomad OTH AF: 0.0880

GnomAD4 exome AF: 0.0824 AC: 52745 AN: 640276 Hom.: 2740 AF XY: 0.0824 AC XY: 28329 AN XY: 343652

African (AFR) AF: 0.0449 AC: 720 AN: 16048

American (AMR) AF: 0.0898 AC: 3122 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2210 AN: 20402

East Asian (EAS) AF: 0.196 AC: 6337 AN: 32304

South Asian (SAS) AF: 0.0832 AC: 5299 AN: 63666

European-Finnish (FIN) AF: 0.0604 AC: 2733 AN: 45220

Middle Eastern (MID) AF: 0.0905 AC: 375 AN: 4144

European-Non Finnish (NFE) AF: 0.0739 AC: 28869 AN: 390570

Other (OTH) AF: 0.0928 AC: 3080 AN: 33172

GnomAD4 genome AF: 0.0782 AC: 11842 AN: 151440 Hom.: 531 Cov.: 31 AF XY: 0.0801 AC XY: 5926 AN XY: 73994

African (AFR) AF: 0.0529 AC: 2175 AN: 41106

American (AMR) AF: 0.0779 AC: 1184 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3468

East Asian (EAS) AF: 0.245 AC: 1264 AN: 5162

South Asian (SAS) AF: 0.0869 AC: 417 AN: 4798

European-Finnish (FIN) AF: 0.0609 AC: 640 AN: 10510

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.0817 AC: 5543 AN: 67884

Other (OTH) AF: 0.0928 AC: 195 AN: 2102

Alfa AF: 0.0332 Hom.: 18

Bravo AF: 0.0793

Asia WGS AF: 0.199 AC: 690 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 21, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=100/0	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: rs35377745; hg19: chr3-191074783; COSMIC: COSV101165373; COSMIC: COSV101165373;