rs4677729

Variant names:

• chr3-191375595-A-G
• rs4677729
• NM_178335.3:c.976+6A>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+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,610,156 control chromosomes in the GnomAD database, including 137,770 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18886 hom., cov: 30)
  • Exomes 𝑓: 0.40 (118884 hom.)
• Consequence: CCDC50 NM_178335.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001828
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.280
• Publications: 15 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=-0.83).
• BP6: Variant 3-191375595-A-G is Benign according to our data. Variant chr3-191375595-A-G is described in ClinVar as Benign. ClinVar VariationId is 48160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.676 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+6A>G		splice_region intron	N/A	NP_848018.1	Q8IVM0-2
	CCDC50	NM_174908.4		c.449-4564A>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+6A>G		splice_region intron	N/A	ENSP00000376249.4	Q8IVM0-2
	CCDC50	ENST00000392456.4	TSL:1	c.449-4564A>G		intron	N/A	ENSP00000376250.4	Q8IVM0-1
	CCDC50	ENST00000899243.1		c.976+6A>G		splice_region intron	N/A	ENSP00000569302.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73225 AN: 151700 Hom.: 18860 Cov.: 30

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.454

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.425 AC: 104123 AN: 245184 AF XY: 0.413

Gnomad AFR exome AF: 0.681

Gnomad AMR exome AF: 0.494

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.452

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.400 AC: 583884 AN: 1458336 Hom.: 118884 Cov.: 39 AF XY: 0.397 AC XY: 288197 AN XY: 725310

African (AFR) AF: 0.684 AC: 22819 AN: 33372

American (AMR) AF: 0.494 AC: 21810 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 11963 AN: 26064

East Asian (EAS) AF: 0.410 AC: 16216 AN: 39526

South Asian (SAS) AF: 0.359 AC: 30901 AN: 86018

European-Finnish (FIN) AF: 0.368 AC: 19581 AN: 53216

Middle Eastern (MID) AF: 0.386 AC: 2189 AN: 5664

European-Non Finnish (NFE) AF: 0.391 AC: 433487 AN: 1110064

Other (OTH) AF: 0.414 AC: 24918 AN: 60226

GnomAD4 genome AF: 0.483 AC: 73311 AN: 151820 Hom.: 18886 Cov.: 30 AF XY: 0.481 AC XY: 35682 AN XY: 74170

African (AFR) AF: 0.683 AC: 28253 AN: 41394

American (AMR) AF: 0.472 AC: 7199 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1600 AN: 3468

East Asian (EAS) AF: 0.453 AC: 2326 AN: 5130

South Asian (SAS) AF: 0.351 AC: 1679 AN: 4790

European-Finnish (FIN) AF: 0.372 AC: 3929 AN: 10554

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26983 AN: 67928

Other (OTH) AF: 0.458 AC: 969 AN: 2114

Alfa AF: 0.432 Hom.: 7161

Bravo AF: 0.503

Asia WGS AF: 0.440 AC: 1528 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	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	-0.83
CADD	Benign	1.3
DANN	Benign	0.52
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.012
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: rs4677729; hg19: chr3-191093384; COSMIC: COSV66668397;