3-191375362-A-G

Variant names:

• chr3-191375362-A-G
• rs727502916
• NM_178335.3:c.749A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_178335.3(CCDC50):​c.749A>G​(p.Glu250Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E250Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC50 NM_178335.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.377
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029440135).
• BP6: Variant 3-191375362-A-G is Benign according to our data. Variant chr3-191375362-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 162856.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	NM_178335.3	MANE Select	c.749A>G	p.Glu250Gly	missense	Exon 6 of 12	NP_848018.1
	CCDC50	NM_174908.4		c.449-4797A>G		intron	N/A	NP_777568.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC50	ENST00000392455.9	TSL:1 MANE Select	c.749A>G	p.Glu250Gly	missense	Exon 6 of 12	ENSP00000376249.4
	CCDC50	ENST00000392456.4	TSL:1	c.449-4797A>G		intron	N/A	ENSP00000376250.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 10, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu250Gly in Exon 6 of CCDC50: This variant is not expected to have clinical si gnificance due to a lack of conservation across species. Of note, several mammal s, including cat, dog, and ferret have a glycine (Gly) at this position despite high nearby amino acid conservation. In addition, computational analyses (AlignG VGD, PolyPhen2, and SIFT) do not suggest a high likelihood of impact to the prot ein.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.92
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.38
PrimateAI	Benign	0.28	T
Polyphen		0.0010	B
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0166)
ClinPred		0.29	T
GERP RS		-3.5
gMVP		0.053
Mutation Taster		=90/10	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: rs727502916; hg19: chr3-191093151;