rs117419007

Variant names:

• chr17-80047356-C-T
• rs117419007
• NM_017950.4:c.630C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_017950.4(CCDC40):​c.630C>T​(p.Ser210Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,613,620 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (41 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.244

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]

ENSG00000289689 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-80047356-C-T is Benign according to our data. Variant chr17-80047356-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197317.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.244 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00478 (728/152296) while in subpopulation NFE AF= 0.00566 (385/68018). AF 95% confidence interval is 0.00519. There are 5 homozygotes in gnomad4. There are 368 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.630C>T	p.Ser210Ser	synonymous_variant	Exon 4 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.630C>T	p.Ser210Ser	synonymous_variant	Exon 4 of 18		NP_001230271.1
CCDC40	NM_001330508.2	c.630C>T	p.Ser210Ser	synonymous_variant	Exon 4 of 11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.630C>T	p.Ser210Ser	synonymous_variant	Exon 4 of 20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 727 AN: 152178 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00564

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00598 AC: 1484 AN: 248064 Hom.: 8 AF XY: 0.00603 AC XY: 813 AN XY: 134846

Gnomad AFR exome AF: 0.000976

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00550

Gnomad FIN exome AF: 0.0219

Gnomad NFE exome AF: 0.00582

Gnomad OTH exome AF: 0.00564

GnomAD4 exome AF: 0.00604 AC: 8821 AN: 1461324 Hom.: 41 Cov.: 33 AF XY: 0.00604 AC XY: 4388 AN XY: 726986

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00517

Gnomad4 FIN exome AF: 0.0224

Gnomad4 NFE exome AF: 0.00587

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152296 Hom.: 5 Cov.: 33 AF XY: 0.00494 AC XY: 368 AN XY: 74478

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.00566

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00487 Hom.: 5

Bravo AF: 0.00356

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00540

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Feb 17, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCDC40: BP4, BP7, BS2 -

Nov 05, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 15 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.9
DANN	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs117419007; hg19: chr17-78021155;