chr3-191375645-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

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.976+56A>G		intron_variant	Intron 6 of 11	ENST00000392455.9	NP_848018.1
CCDC50	NM_174908.4	c.449-4514A>G		intron_variant	Intron 5 of 10		NP_777568.1
CCDC50	XM_011512460.2	c.976+56A>G		intron_variant	Intron 6 of 7		XP_011510762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.976+56A>G		intron_variant	Intron 6 of 11	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.449-4514A>G		intron_variant	Intron 5 of 10	1		ENSP00000376250.4

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

Gnomad4 AFR exome AF: 0.822 AC: 25953 AN: 31590

Gnomad4 AMR exome AF: 0.739 AC: 29002 AN: 39260

Gnomad4 ASJ exome AF: 0.548 AC: 13785 AN: 25170

Gnomad4 EAS exome AF: 0.891 AC: 33457 AN: 37546

Gnomad4 SAS exome AF: 0.678 AC: 55124 AN: 81334

Gnomad4 FIN exome AF: 0.552 AC: 28272 AN: 51202

Gnomad4 NFE exome AF: 0.501 AC: 537096 AN: 1072416

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.816 AC: 0.815665 AN: 0.815665

Gnomad4 AMR AF: 0.678 AC: 0.677504 AN: 0.677504

Gnomad4 ASJ AF: 0.543 AC: 0.542939 AN: 0.542939

Gnomad4 EAS AF: 0.918 AC: 0.918023 AN: 0.918023

Gnomad4 SAS AF: 0.693 AC: 0.693495 AN: 0.693495

Gnomad4 FIN AF: 0.563 AC: 0.563211 AN: 0.563211

Gnomad4 NFE AF: 0.515 AC: 0.515239 AN: 0.515239

Gnomad4 OTH AF: 0.598 AC: 0.59763 AN: 0.59763

Alfa AF: 0.602 Hom.: 4164

Bravo AF: 0.655

Asia WGS AF: 0.805 AC: 2794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal dominant nonsyndromic hearing loss 44 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.67
DANN	Benign	0.54
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

Publications

LitVar

Other links and lift over

dbSNP: rs293806; hg19: chr3-191093434;