rs201709592

Positions:

• chr17-80040052-A-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.334A>G​(p.Thr112Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00397 in 1,614,104 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T112K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (16 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.981

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=0.0055594146).
• BP6: Variant 17-80040052-A-G is Benign according to our data. Variant chr17-80040052-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166808.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=2, Uncertain_significance=1}. Variant chr17-80040052-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00249 (379/152342) while in subpopulation NFE AF= 0.00406 (276/68026). AF 95% confidence interval is 0.00366. There are 0 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.334A>G	p.Thr112Ala	missense_variant	3/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.334A>G	p.Thr112Ala	missense_variant	3/18
CCDC40	NM_001330508.2	c.334A>G	p.Thr112Ala	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.334A>G	p.Thr112Ala	missense_variant	3/20	5	NM_017950.4	P2

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00236 AC: 585 AN: 248092 Hom.: 4 AF XY: 0.00250 AC XY: 337 AN XY: 134734

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00381

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00413 AC: 6036 AN: 1461762 Hom.: 16 Cov.: 33 AF XY: 0.00399 AC XY: 2900 AN XY: 727212

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00487

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74496

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00406

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00362 Hom.: 0

Bravo AF: 0.00238

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000770 AC: 3

ESP6500EA AF: 0.00362 AC: 30

ExAC AF: 0.00232 AC: 280

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 15 Uncertain:1 Benign: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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 06, 2015	p.Thr112Ala in exon 3 of CCDC40: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (200/66682) of European chrom osomes, including 3 homozygotes, by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs201709592). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

CCDC40: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.29
DANN	Benign	0.55
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.50	T;T;T;T;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.0056	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.45	N;N;N;N;.;.
REVEL	Benign	0.017
Sift	Benign	0.68	T;T;T;T;.;.
Sift4G	Benign	0.89	T;T;T;T;D;T
Polyphen		0.0030, 0.015	.;B;.;B;.;.
Vest4		0.035
MVP		0.040
MPC		0.17
ClinPred		0.0011	T
GERP RS		-5.5
Varity_R		0.019
gMVP		0.12

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: rs201709592; hg19: chr17-78013851;