rs371071557

chr17-80050229-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_017950.4(CCDC40):c.1105G>A(p.Ala369Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000631 in 1,600,476 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.617

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024003536).
• BP6: Variant 17-80050229-G-A is Benign according to our data. Variant chr17-80050229-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 566968.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.1105G>A	p.Ala369Thr	missense_variant	7/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.1105G>A	p.Ala369Thr	missense_variant	7/18
CCDC40	NM_001330508.2	c.1105G>A	p.Ala369Thr	missense_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.1105G>A	p.Ala369Thr	missense_variant	7/20	5	NM_017950.4	P2
	ENST00000695611.1	n.1432-2710C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000857 AC: 13 AN: 151772 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

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: 0.0000589

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000184 AC: 41 AN: 222580 Hom.: 0 AF XY: 0.000156 AC XY: 19 AN XY: 122122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000976

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000615

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000513

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.0000607 AC: 88 AN: 1448704 Hom.: 0 Cov.: 34 AF XY: 0.0000611 AC XY: 44 AN XY: 720080

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000888

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.0000837

GnomAD4 genome AF: 0.0000857 AC: 13 AN: 151772 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74114

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000236 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000166 AC: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 19, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 369 of the CCDC40 protein (p.Ala369Thr). This variant is present in population databases (rs371071557, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CCDC40-related conditions. ClinVar contains an entry for this variant (Variation ID: 566968). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CCDC40 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Primary ciliary dyskinesia 15 Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.2
Dann	Benign	0.95
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.030	N;N;N;N
REVEL	Benign	0.0080
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.032, 0.23	.;B;.;B
Vest4		0.10
MVP		0.048
MPC		0.17
ClinPred		0.021	T
GERP RS		-1.4
Varity_R		0.032
gMVP		0.064

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: rs371071557; hg19: chr17-78024028; COSMIC: COSV53903537; COSMIC: COSV53903537;