Genetic Variant NM_178335.3:c.50-69delA (chr3-191357007-TA-T) – ACMG Classification: Likely_benign (-4 pts)

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.389

Publications

0 publications found

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 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

CCDC50 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 366 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3 link	c.50-69delA	intron_variant	Intron 1 of 11	ENST00000392455.9	NP_848018.1	Q8IVM0-2
CCDC50	NM_174908.4 link	c.50-69delA	intron_variant	Intron 1 of 10		NP_777568.1	Q8IVM0-1
CCDC50	XM_011512460.2 link	c.50-69delA	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 link	c.50-80delA		intron_variant	Intron 1 of 11	1	NM_178335.3	ENSP00000376249.4		Q8IVM0-2
CCDC50	ENST00000392456.4 link	c.50-80delA		intron_variant	Intron 1 of 10	1		ENSP00000376250.4		Q8IVM0-1

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

364

AN:

145410

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.266

AC XY:

57152

AN XY:

215130

show subpopulations

⚠️ 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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.260

Heterozygous variant carriers

12972

25945

38917

51890

64862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00252

AC:

366

AN:

145474

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

206

AN XY:

70708

show subpopulations

African (AFR)

AF:

0.00416

AC:

167

AN:

40112

American (AMR)

AF:

0.00397

AC:

AN:

14604

Ashkenazi Jewish (ASJ)

AF:

0.00118

AC:

AN:

3382

East Asian (EAS)

AF:

0.000791

AC:

AN:

5058

South Asian (SAS)

AF:

0.00174

AC:

AN:

4586

European-Finnish (FIN)

AF:

0.00391

AC:

AN:

8944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00136

AC:

AN:

65620

Other (OTH)

AF:

0.000503

AC:

AN:

1990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000387

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.39

Mutation Taster

=100/0

polymorphism

(source)

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

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NM_178335.3:c.50-69delA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over