rs4889815

chr17-80088073-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017950.4(CCDC40):c.2682G>A(p.Ala894=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,594 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 32)
  • Exomes 𝑓: 0.011 (183 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.923

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-80088073-G-A is Benign according to our data. Variant chr17-80088073-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80088073-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.923 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.01 (1521/151990) while in subpopulation EAS AF= 0.0364 (188/5170). AF 95% confidence interval is 0.0321. There are 15 homozygotes in gnomad4. There are 786 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.2682G>A	p.Ala894=	synonymous_variant	16/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.2682G>A	p.Ala894=	synonymous_variant	16/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.2682G>A	p.Ala894=	synonymous_variant	16/20	5	NM_017950.4	P2

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1522 AN: 151872 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0371

Gnomad SAS AF: 0.00915

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00883

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.0146 AC: 3643 AN: 249398 Hom.: 46 AF XY: 0.0132 AC XY: 1792 AN XY: 135346

Gnomad AFR exome AF: 0.00569

Gnomad AMR exome AF: 0.0311

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.0352

Gnomad SAS exome AF: 0.00418

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.00997

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0112 AC: 16403 AN: 1461604 Hom.: 183 Cov.: 34 AF XY: 0.0109 AC XY: 7890 AN XY: 727124

Gnomad4 AFR exome AF: 0.00436

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.00524

Gnomad4 EAS exome AF: 0.0510

Gnomad4 SAS exome AF: 0.00444

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.00964

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0100 AC: 1521 AN: 151990 Hom.: 15 Cov.: 32 AF XY: 0.0106 AC XY: 786 AN XY: 74278

Gnomad4 AFR AF: 0.00611

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.0364

Gnomad4 SAS AF: 0.00916

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.00883

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00840 Hom.: 4

Bravo AF: 0.00991

Asia WGS AF: 0.0360 AC: 124 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 05, 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. -

Primary ciliary dyskinesia 15 Benign:2

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

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

Apr 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	5.8
Dann	Benign	0.42

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: rs4889815; hg19: chr17-78061872; COSMIC: COSV66473177; COSMIC: COSV66473177;