rs2289532

chr17-80050268-G-A

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.1144G>A(p.Glu382Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,566,090 control chromosomes in the GnomAD database, including 18 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E382D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (15 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.840

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005613655).
• BP6: Variant 17-80050268-G-A is Benign according to our data. Variant chr17-80050268-G-A is described in ClinVar as [Benign]. Clinvar id is 226487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000703 (107/152280) while in subpopulation EAS AF= 0.0178 (92/5172). AF 95% confidence interval is 0.0149. There are 3 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.1144G>A	p.Glu382Lys	missense_variant	7/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.1144G>A	p.Glu382Lys	missense_variant	7/18
CCDC40	NM_001330508.2	c.1144G>A	p.Glu382Lys	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.1144G>A	p.Glu382Lys	missense_variant	7/20	5	NM_017950.4	P2
	ENST00000695611.1	n.1432-2749C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152162 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00178 AC: 302 AN: 169920 Hom.: 4 AF XY: 0.00178 AC XY: 163 AN XY: 91604

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.0000386

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0224

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0000612

Gnomad NFE exome AF: 0.0000579

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000864 AC: 1221 AN: 1413810 Hom.: 15 Cov.: 34 AF XY: 0.000878 AC XY: 614 AN XY: 699470

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0296

Gnomad4 SAS exome AF: 0.000876

Gnomad4 FIN exome AF: 0.000201

Gnomad4 NFE exome AF: 0.0000193

Gnomad4 OTH exome AF: 0.000444

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152280 Hom.: 3 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00117 Hom.: 4

Bravo AF: 0.000699

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00125 AC: 146

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 15, 2019	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	Invitae	Dec 18, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Glu382Lys in exon 7 of CCDC40: This variant is not expected to have clinical sig nificance because it has been identified in 5.2% (10/194) of Han Chinese chromos omes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.ni h.gov/projects/SNP; dbSNP rs2289532). -

Primary ciliary dyskinesia 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	15
Dann	Benign	0.92
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.80	T;T;T;T
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.35, 0.98	.;B;.;D
Vest4		0.23
MVP		0.14
MPC		0.21
ClinPred		0.020	T
GERP RS		1.5
Varity_R		0.079
gMVP		0.058

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: rs2289532; hg19: chr17-78024067; COSMIC: COSV53901275; COSMIC: COSV53901275;