rs115850223

Positions:

• chr17-80084770-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017950.4(CCDC40):​c.2017G>A​(p.Asp673Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,614,080 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.35

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]

CCDC40 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007947803).
• BP6: Variant 17-80084770-G-A is Benign according to our data. Variant chr17-80084770-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215897.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00276 (421/152270) while in subpopulation AFR AF= 0.00961 (399/41534). AF 95% confidence interval is 0.00883. There are 1 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.2017G>A	p.Asp673Asn	missense_variant	13/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.2017G>A	p.Asp673Asn	missense_variant	13/18		NP_001230271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.2017G>A	p.Asp673Asn	missense_variant	13/20	5	NM_017950.4	ENSP00000380679.4
CCDC40	ENST00000574799.5	n.1554G>A		non_coding_transcript_exon_variant	9/16	1
CCDC40	ENST00000374877.7	c.2017G>A	p.Asp673Asn	missense_variant	13/18	5		ENSP00000364011.3
CCDC40	ENST00000572253.5	n.644G>A		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000734 AC: 183 AN: 249376 Hom.: 0 AF XY: 0.000554 AC XY: 75 AN XY: 135302

Gnomad AFR exome AF: 0.00918

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000350 AC: 511 AN: 1461810 Hom.: 4 Cov.: 32 AF XY: 0.000305 AC XY: 222 AN XY: 727208

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.00276 AC: 421 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.00242 AC XY: 180 AN XY: 74464

Gnomad4 AFR AF: 0.00961

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000524 Hom.: 1

Bravo AF: 0.00326

ESP6500AA AF: 0.00609 AC: 25

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.000892 AC: 108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 04, 2021	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

Primary ciliary dyskinesia 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, 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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CCDC40 p.Asp673Asn variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs115850223), ClinVar (classified as likely benign by Invitae and as a VUS by Illumina Clinical Services for ciliary dyskinesia) and in LOVD 3.0 (classified as likely benign). The variant was also identified in control databases in 258 of 280770 chromosomes at a frequency of 0.000919 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 215 of 24180 chromosomes (freq: 0.008892), Latino in 31 of 35360 chromosomes (freq: 0.000877), Other in 2 of 7146 chromosomes (freq: 0.00028), European (non-Finnish) in 9 of 128602 chromosomes (freq: 0.00007) and South Asian in 1 of 30594 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish, East Asian or European (Finnish) populations. The variant occurs outside of the splicing consensus sequence however in silico or computational prediction software programs, (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. The p.Asp673 residue is not conserved in mammals however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.39	.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.80
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.15
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.022	D;D
Polyphen		0.078	.;B
Vest4		0.29
MVP		0.19
MPC		0.18
ClinPred		0.020	T
GERP RS		0.93
Varity_R		0.078
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115850223; hg19: chr17-78058569;