rs2028572

Variant names:

• chr3-191375264-T-C
• rs2028572
• NM_178335.3:c.651T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_178335.3(CCDC50):​c.651T>C​(p.His217His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,613,266 control chromosomes in the GnomAD database, including 138,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18933 hom., cov: 32)
  • Exomes 𝑓: 0.40 (119346 hom.)
• Consequence: CCDC50 NM_178335.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.02
• Publications: 28 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 3-191375264-T-C is Benign according to our data. Variant chr3-191375264-T-C is described in ClinVar as Benign. ClinVar VariationId is 48156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.02 with no splicing effect.
• 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.651T>C	p.His217His	synonymous	Exon 6 of 12	NP_848018.1
	CCDC50	NM_174908.4		c.449-4895T>C		intron	N/A	NP_777568.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	ENST00000392455.9	TSL:1 MANE Select	c.651T>C	p.His217His	synonymous	Exon 6 of 12	ENSP00000376249.4
	CCDC50	ENST00000392456.4	TSL:1	c.449-4895T>C		intron	N/A	ENSP00000376250.4
	CCDC50	ENST00000899243.1		c.651T>C	p.His217His	synonymous	Exon 6 of 13	ENSP00000569302.1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73370 AN: 151824 Hom.: 18907 Cov.: 32

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.428 AC: 107004 AN: 250000 AF XY: 0.416

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 0.497

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.454

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.395

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.401 AC: 585556 AN: 1461324 Hom.: 119346 Cov.: 51 AF XY: 0.398 AC XY: 289105 AN XY: 726972

African (AFR) AF: 0.684 AC: 22874 AN: 33442

American (AMR) AF: 0.496 AC: 22133 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 11994 AN: 26116

East Asian (EAS) AF: 0.410 AC: 16279 AN: 39670

South Asian (SAS) AF: 0.360 AC: 31016 AN: 86242

European-Finnish (FIN) AF: 0.368 AC: 19662 AN: 53370

Middle Eastern (MID) AF: 0.388 AC: 2232 AN: 5760

European-Non Finnish (NFE) AF: 0.391 AC: 434375 AN: 1111722

Other (OTH) AF: 0.414 AC: 24991 AN: 60354

GnomAD4 genome AF: 0.483 AC: 73456 AN: 151942 Hom.: 18933 Cov.: 32 AF XY: 0.482 AC XY: 35762 AN XY: 74228

African (AFR) AF: 0.683 AC: 28335 AN: 41498

American (AMR) AF: 0.473 AC: 7206 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3470

East Asian (EAS) AF: 0.455 AC: 2338 AN: 5138

South Asian (SAS) AF: 0.352 AC: 1692 AN: 4810

European-Finnish (FIN) AF: 0.374 AC: 3938 AN: 10540

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.398 AC: 27001 AN: 67916

Other (OTH) AF: 0.458 AC: 970 AN: 2116

Alfa AF: 0.435 Hom.: 48662

Bravo AF: 0.503

Asia WGS AF: 0.440 AC: 1529 AN: 3478

EpiCase AF: 0.395

EpiControl AF: 0.392

ClinVar

ClinVar submissions as Germline

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	-0.94
CADD	Benign	0.030
DANN	Benign	0.35
PhyloP100		-3.0
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: rs2028572; hg19: chr3-191093053; COSMIC: COSV66667458; COSMIC: COSV66667458;