rs191736683

chr17-80081656-C-G

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.1673C>G(p.Thr558Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,614,206 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (3 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.0880

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008179367).
• BP6: Variant 17-80081656-C-G is Benign according to our data. Variant chr17-80081656-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215523.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2, Likely_benign=2}. Variant chr17-80081656-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00332 (4853/1461858) while in subpopulation NFE AF= 0.00404 (4489/1112008). AF 95% confidence interval is 0.00394. There are 3 homozygotes in gnomad4_exome. There are 2282 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.1673C>G	p.Thr558Arg	missense_variant	11/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.1673C>G	p.Thr558Arg	missense_variant	11/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.1673C>G	p.Thr558Arg	missense_variant	11/20	5	NM_017950.4	P2
CCDC40	ENST00000574799.5	n.1210C>G		non_coding_transcript_exon_variant	7/16	1
CCDC40	ENST00000374877.7	c.1673C>G	p.Thr558Arg	missense_variant	11/18	5		A2
CCDC40	ENST00000572253.5	n.214C>G		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152230 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00186 AC: 463 AN: 249330 Hom.: 1 AF XY: 0.00184 AC XY: 249 AN XY: 135370

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000458

Gnomad FIN exome AF: 0.00445

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00332 AC: 4853 AN: 1461858 Hom.: 3 Cov.: 31 AF XY: 0.00314 AC XY: 2282 AN XY: 727232

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00339

Gnomad4 NFE exome AF: 0.00404

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152348 Hom.: 2 Cov.: 33 AF XY: 0.00208 AC XY: 155 AN XY: 74490

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00443

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00276 Hom.: 1

Bravo AF: 0.00165

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.00284 AC: 24

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2017	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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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 specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 20, 2016

p.Thr558Arg in exon 11 of CCDC40: This variant is not expected to have clinical significance because it has been identified in 0.5% (35/6606) of Finnish chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs191736683). -

CCDC40-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	3.6
Dann	Benign	0.56
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.021
Sift	Benign	0.45	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.38	.;B
Vest4		0.20
MVP		0.081
MPC		0.27
ClinPred		0.0031	T
GERP RS		-2.8
Varity_R		0.094
gMVP		0.46

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: rs191736683; hg19: chr17-78055455; COSMIC: COSV105930497;