chr3-191357007-TAAA-T

Variant names:

• chr3-191357007-TAAA-T
• rs879004278
• NM_178335.3:c.50-71_50-69delAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178335.3(CCDC50):​c.50-71_50-69delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000162 in 616,818 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.50-71_50-69delAAA		intron_variant	Intron 1 of 11	ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.50-71_50-69delAAA		intron_variant	Intron 1 of 10		NP_777568.1
CCDC50	XM_011512460.2	c.50-71_50-69delAAA		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_50-78delAAA		intron_variant	Intron 1 of 11	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.50-80_50-78delAAA		intron_variant	Intron 1 of 10	1		ENSP00000376250.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000162 AC: 1 AN: 616818 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 328732

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

African (AFR) AF: 0.00 AC: 0 AN: 14828

American (AMR) AF: 0.00 AC: 0 AN: 31186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17534

East Asian (EAS) AF: 0.00 AC: 0 AN: 27170

South Asian (SAS) AF: 0.00 AC: 0 AN: 56088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3824

European-Non Finnish (NFE) AF: 0.00000252 AC: 1 AN: 396404

Other (OTH) AF: 0.00 AC: 0 AN: 30288

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

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;