chr3-191357007-T-TA

Variant names:

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

Variant summary

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

The NM_178335.3(CCDC50):​c.50-69dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 753,264 control chromosomes in the GnomAD database, including 121 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (119 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (2 hom.)
• Consequence: CCDC50 NM_178335.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 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 3-191357007-T-TA is Benign according to our data. Variant chr3-191357007-T-TA is described in ClinVar as [Benign]. Clinvar id is 1271942.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.50-69dupA		intron_variant	Intron 1 of 11	ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.50-69dupA		intron_variant	Intron 1 of 10		NP_777568.1
CCDC50	XM_011512460.2	c.50-69dupA		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.50-81_50-80insA		intron_variant	Intron 1 of 11	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.50-81_50-80insA		intron_variant	Intron 1 of 10	1		ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3364 AN: 145980 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.000217

Gnomad FIN AF: 0.000109

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000394

Gnomad OTH AF: 0.0121

GnomAD4 exome AF: 0.00830 AC: 5039 AN: 607210 Hom.: 2 AF XY: 0.00745 AC XY: 2411 AN XY: 323662

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

African (AFR) AF: 0.0818 AC: 1195 AN: 14614

American (AMR) AF: 0.00763 AC: 235 AN: 30796

Ashkenazi Jewish (ASJ) AF: 0.00320 AC: 55 AN: 17214

East Asian (EAS) AF: 0.00288 AC: 77 AN: 26720

South Asian (SAS) AF: 0.00287 AC: 159 AN: 55404

European-Finnish (FIN) AF: 0.00446 AC: 173 AN: 38776

Middle Eastern (MID) AF: 0.00606 AC: 23 AN: 3798

European-Non Finnish (NFE) AF: 0.00711 AC: 2774 AN: 390076

Other (OTH) AF: 0.0117 AC: 348 AN: 29812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0231 AC: 3369 AN: 146054 Hom.: 119 Cov.: 32 AF XY: 0.0234 AC XY: 1665 AN XY: 71022

African (AFR) AF: 0.0789 AC: 3165 AN: 40134

American (AMR) AF: 0.0102 AC: 150 AN: 14648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5064

South Asian (SAS) AF: 0.000218 AC: 1 AN: 4592

European-Finnish (FIN) AF: 0.000109 AC: 1 AN: 9146

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.000395 AC: 26 AN: 65898

Other (OTH) AF: 0.0120 AC: 24 AN: 1998

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 18, 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		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;