rs183809462

Positions:

• chr17-80086103-G-A
• chr17-80086103-G-T

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.2336G>A​(p.Arg779His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000832 in 1,614,142 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R779L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (4 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.03

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=0.0105339885).
• BP6: Variant 17-80086103-G-A is Benign according to our data. Variant chr17-80086103-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00367 (559/152288) while in subpopulation AFR AF= 0.0123 (513/41562). AF 95% confidence interval is 0.0115. There are 3 homozygotes in gnomad4. There are 265 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.2336G>A	p.Arg779His	missense_variant	14/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.2336G>A	p.Arg779His	missense_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.2336G>A	p.Arg779His	missense_variant	14/20	5	NM_017950.4	P2
CCDC40	ENST00000574799.5	n.1873G>A		non_coding_transcript_exon_variant	10/16	1
CCDC40	ENST00000374877.7	c.2336G>A	p.Arg779His	missense_variant	14/18	5		A2
CCDC40	ENST00000572253.5	n.963G>A		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes AF: 0.00368 AC: 560 AN: 152170 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00118 AC: 293 AN: 249328 Hom.: 2 AF XY: 0.000960 AC XY: 130 AN XY: 135358

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000536 AC: 784 AN: 1461854 Hom.: 4 Cov.: 32 AF XY: 0.000462 AC XY: 336 AN XY: 727226

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00367 AC: 559 AN: 152288 Hom.: 3 Cov.: 32 AF XY: 0.00356 AC XY: 265 AN XY: 74464

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00149 Hom.: 3

Bravo AF: 0.00398

ESP6500AA AF: 0.0102 AC: 43

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2018	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 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2020

- -

Primary ciliary dyskinesia 15 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.11
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		1.0	.;D
Vest4		0.28
MVP		0.55
MPC		0.27
ClinPred		0.039	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.16

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: rs183809462; hg19: chr17-78059902;