chr3-191380871-A-G

Variant names:

• chr3-191380871-A-G
• rs114502673
• NM_178335.3:c.1181A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178335.3(CCDC50):​c.1181A>G​(p.Lys394Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00623 in 1,613,084 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (89 hom.)
• Consequence: CCDC50 NM_178335.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.09
• Publications: 12 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 (MetaRNN=0.006295413).
• BP6: Variant 3-191380871-A-G is Benign according to our data. Variant chr3-191380871-A-G is described in ClinVar as Benign. ClinVar VariationId is 162860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00385 (586/152226) while in subpopulation SAS AF = 0.023 (111/4830). AF 95% confidence interval is 0.0195. There are 4 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 586 AD,Unknown gene.

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.1181A>G	p.Lys394Arg	missense	Exon 9 of 12	NP_848018.1	Q8IVM0-2
	CCDC50	NM_174908.4		c.653A>G	p.Lys218Arg	missense	Exon 8 of 11	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.1181A>G	p.Lys394Arg	missense	Exon 9 of 12	ENSP00000376249.4	Q8IVM0-2
	CCDC50	ENST00000392456.4	TSL:1	c.653A>G	p.Lys218Arg	missense	Exon 8 of 11	ENSP00000376250.4	Q8IVM0-1
	CCDC50	ENST00000899243.1		c.1268A>G	p.Lys423Arg	missense	Exon 10 of 13	ENSP00000569302.1

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 583 AN: 152108 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00605 AC: 1515 AN: 250402 AF XY: 0.00724

Gnomad AFR exome AF: 0.000929

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00549

Gnomad OTH exome AF: 0.00624

GnomAD4 exome AF: 0.00648 AC: 9468 AN: 1460858 Hom.: 89 Cov.: 33 AF XY: 0.00727 AC XY: 5284 AN XY: 726724

African (AFR) AF: 0.000748 AC: 25 AN: 33434

American (AMR) AF: 0.00157 AC: 70 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00575 AC: 150 AN: 26084

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39652

South Asian (SAS) AF: 0.0258 AC: 2221 AN: 86224

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53398

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5764

European-Non Finnish (NFE) AF: 0.00586 AC: 6517 AN: 1111326

Other (OTH) AF: 0.00654 AC: 395 AN: 60352

GnomAD4 genome AF: 0.00385 AC: 586 AN: 152226 Hom.: 4 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74450

African (AFR) AF: 0.000866 AC: 36 AN: 41562

American (AMR) AF: 0.00177 AC: 27 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00556 AC: 378 AN: 67978

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00365 Hom.: 5

Bravo AF: 0.00344

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00639 AC: 776

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0047	T
Eigen	Benign	0.090
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.1
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.092
Polyphen		0.70	P
MVP		0.39
MPC		0.46
ClinPred		0.019	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.019
Mutation Taster		=91/9	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: rs114502673; hg19: chr3-191098660; COSMIC: COSV99061951;