rs2304854

Positions:

• chr17-80099763-A-G
• chr17-80099763-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017950.4(CCDC40):​c.3417A>G​(p.Pro1139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 1,612,434 control chromosomes in the GnomAD database, including 171,762 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18977 hom., cov: 31)
  • Exomes 𝑓: 0.45 (152785 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.08

Genes affected

CCDC40 (HGNC:26090): (coiled-coil domain 40 molecular ruler complex subunit) This gene encodes a protein that is necessary for motile cilia function. It functions in correct left-right axis formation by regulating the assembly of the inner dynein arm and the dynein regulatory complexes, which control ciliary beat. Mutations in this gene cause ciliary dyskinesia type 15, a disorder due to defects in cilia motility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-80099763-A-G is Benign according to our data. Variant chr17-80099763-A-G is described in ClinVar as [Benign]. Clinvar id is 178712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80099763-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.3417A>G	p.Pro1139=	synonymous_variant	20/20	ENST00000397545.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.3417A>G	p.Pro1139=	synonymous_variant	20/20	5	NM_017950.4	P2
CCDC40	ENST00000574799.5	n.2954A>G		non_coding_transcript_exon_variant	16/16	1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74666 AN: 151786 Hom.: 18954 Cov.: 31

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.437

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.596

Gnomad NFE AF: 0.457

Gnomad OTH AF: 0.466

GnomAD3 exomes AF: 0.451 AC: 111378 AN: 247100 Hom.: 26325 AF XY: 0.461 AC XY: 61985 AN XY: 134524

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.410

Gnomad SAS exome AF: 0.521

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.475

GnomAD4 exome AF: 0.454 AC: 662967 AN: 1460530 Hom.: 152785 Cov.: 50 AF XY: 0.457 AC XY: 331983 AN XY: 726564

Gnomad4 AFR exome AF: 0.615

Gnomad4 AMR exome AF: 0.253

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.454

Gnomad4 SAS exome AF: 0.513

Gnomad4 FIN exome AF: 0.542

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.468

GnomAD4 genome AF: 0.492 AC: 74734 AN: 151904 Hom.: 18977 Cov.: 31 AF XY: 0.491 AC XY: 36484 AN XY: 74242

Gnomad4 AFR AF: 0.605

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.457

Gnomad4 OTH AF: 0.469

Alfa AF: 0.450 Hom.: 22871

Bravo AF: 0.479

EpiCase AF: 0.454

EpiControl AF: 0.453

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Pro1139Pro in exon 20 of CCDC40: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 44.7% (3724/8334) of European American chromosomes from a broad population by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2304854). -

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Primary ciliary dyskinesia 15 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Glycogen storage disease, type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.060
DANN	Benign	0.34

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: rs2304854; hg19: chr17-78073562; COSMIC: COSV56409368; COSMIC: COSV56409368;