chr3-191357007-TAA-T

Variant names:

• chr3-191357007-TAA-T
• rs879004278
• NM_178335.3:c.50-70_50-69delAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_178335.3(CCDC50):​c.50-70_50-69delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 760,064 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: CCDC50 NM_178335.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.73
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.50-70_50-69delAA		intron_variant	Intron 1 of 11	ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.50-70_50-69delAA		intron_variant	Intron 1 of 10		NP_777568.1
CCDC50	XM_011512460.2	c.50-70_50-69delAA		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.50-80_50-79delAA		intron_variant	Intron 1 of 11	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.50-80_50-79delAA		intron_variant	Intron 1 of 10	1		ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 146004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000344 AC: 211 AN: 614060 Hom.: 0 AF XY: 0.000324 AC XY: 106 AN XY: 327344

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

African (AFR) AF: 0.000475 AC: 7 AN: 14750

American (AMR) AF: 0.000581 AC: 18 AN: 31002

Ashkenazi Jewish (ASJ) AF: 0.0000573 AC: 1 AN: 17440

East Asian (EAS) AF: 0.00 AC: 0 AN: 27048

South Asian (SAS) AF: 0.000197 AC: 11 AN: 55940

European-Finnish (FIN) AF: 0.000331 AC: 13 AN: 39226

Middle Eastern (MID) AF: 0.000262 AC: 1 AN: 3814

European-Non Finnish (NFE) AF: 0.000385 AC: 152 AN: 394688

Other (OTH) AF: 0.000265 AC: 8 AN: 30152

⚠️ 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: 0.00000685 AC: 1 AN: 146004 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 70938

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

African (AFR) AF: 0.00 AC: 0 AN: 40058

American (AMR) AF: 0.00 AC: 0 AN: 14630

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65910

Other (OTH) AF: 0.00 AC: 0 AN: 1978

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
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;