rs117203086

Positions:

• chr17-80086022-T-C
• chr17-80086022-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017950.4(CCDC40):​c.2255T>C​(p.Leu752Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,613,976 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (35 hom., cov: 32)
  • Exomes 𝑓: 0.022 (443 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008146107).
• BP6: Variant 17-80086022-T-C is Benign according to our data. Variant chr17-80086022-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 178710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80086022-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2742/152222) while in subpopulation NFE AF= 0.0239 (1624/68018). AF 95% confidence interval is 0.0229. There are 35 homozygotes in gnomad4. There are 1376 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.2255T>C	p.Leu752Pro	missense_variant	14/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.2255T>C	p.Leu752Pro	missense_variant	14/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.2255T>C	p.Leu752Pro	missense_variant	14/20	5	NM_017950.4	ENSP00000380679	P2
CCDC40	ENST00000574799.5	n.1792T>C		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7	c.2255T>C	p.Leu752Pro	missense_variant	14/18	5		ENSP00000364011	A2
CCDC40	ENST00000572253.5	n.882T>C		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2742 AN: 152104 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0185 AC: 4617 AN: 249478 Hom.: 56 AF XY: 0.0188 AC XY: 2549 AN XY: 135392

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.00964

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00957

Gnomad FIN exome AF: 0.0458

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0223 AC: 32614 AN: 1461754 Hom.: 443 Cov.: 31 AF XY: 0.0219 AC XY: 15950 AN XY: 727174

Gnomad4 AFR exome AF: 0.00353

Gnomad4 AMR exome AF: 0.00935

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.0423

Gnomad4 NFE exome AF: 0.0244

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0180 AC: 2742 AN: 152222 Hom.: 35 Cov.: 32 AF XY: 0.0185 AC XY: 1376 AN XY: 74428

Gnomad4 AFR AF: 0.00448

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0521

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.0203 Hom.: 45

Bravo AF: 0.0149

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00475 AC: 18

ESP6500EA AF: 0.0247 AC: 203

ExAC AF: 0.0182 AC: 2194

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0239

EpiControl AF: 0.0235

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu752Pro in exon 14 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 2.5% (203/8208) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs117203086). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 09, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 15 Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.50	.;P
Vest4		0.52
MPC		0.47
ClinPred		0.026	T
GERP RS		4.7
Varity_R		0.86
gMVP		0.86

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: rs117203086; hg19: chr17-78059821;