3-191375645-A-G

Variant names:

• chr3-191375645-A-G
• rs293806
• NM_178335.3:c.976+56A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178335.3(CCDC50):​c.976+56A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,553,668 control chromosomes in the GnomAD database, including 244,167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (32370 hom., cov: 31)
  • Exomes 𝑓: 0.54 (211797 hom.)
• Consequence: CCDC50 NM_178335.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.381
• Publications: 6 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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss 44

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-191375645-A-G is Benign according to our data. Variant chr3-191375645-A-G is described in ClinVar as Benign. ClinVar VariationId is 1192702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178335.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	NM_178335.3	MANE Select	c.976+56A>G		intron	N/A	NP_848018.1	Q8IVM0-2
	CCDC50	NM_174908.4		c.449-4514A>G		intron	N/A	NP_777568.1	Q8IVM0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	ENST00000392455.9	TSL:1 MANE Select	c.976+56A>G		intron	N/A	ENSP00000376249.4	Q8IVM0-2
	CCDC50	ENST00000392456.4	TSL:1	c.449-4514A>G		intron	N/A	ENSP00000376250.4	Q8IVM0-1
	CCDC50	ENST00000899243.1		c.976+56A>G		intron	N/A	ENSP00000569302.1

Frequencies

GnomAD3 genomes AF: 0.637 AC: 96652 AN: 151778 Hom.: 32305 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.918

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.599

GnomAD4 exome AF: 0.541 AC: 758164 AN: 1401770 Hom.: 211797 AF XY: 0.543 AC XY: 378268 AN XY: 696028

African (AFR) AF: 0.822 AC: 25953 AN: 31590

American (AMR) AF: 0.739 AC: 29002 AN: 39260

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 13785 AN: 25170

East Asian (EAS) AF: 0.891 AC: 33457 AN: 37546

South Asian (SAS) AF: 0.678 AC: 55124 AN: 81334

European-Finnish (FIN) AF: 0.552 AC: 28272 AN: 51202

Middle Eastern (MID) AF: 0.516 AC: 2549 AN: 4936

European-Non Finnish (NFE) AF: 0.501 AC: 537096 AN: 1072416

Other (OTH) AF: 0.565 AC: 32926 AN: 58316

GnomAD4 genome AF: 0.637 AC: 96776 AN: 151898 Hom.: 32370 Cov.: 31 AF XY: 0.645 AC XY: 47850 AN XY: 74204

African (AFR) AF: 0.816 AC: 33793 AN: 41430

American (AMR) AF: 0.678 AC: 10336 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1884 AN: 3470

East Asian (EAS) AF: 0.918 AC: 4737 AN: 5160

South Asian (SAS) AF: 0.693 AC: 3326 AN: 4796

European-Finnish (FIN) AF: 0.563 AC: 5943 AN: 10552

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 34994 AN: 67918

Other (OTH) AF: 0.598 AC: 1261 AN: 2110

Alfa AF: 0.602 Hom.: 4164

Bravo AF: 0.655

Asia WGS AF: 0.805 AC: 2794 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 44 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.67
DANN	Benign	0.54
PhyloP100		-0.38
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: rs293806; hg19: chr3-191093434;