rs59978698

chr17-80065575-G-Achr17-80065575-G-Cchr17-80065575-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.1531G>A(p.Glu511Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,612,864 control chromosomes in the GnomAD database, including 24 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. E511Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (10 hom., cov: 29)
  • Exomes 𝑓: 0.00064 (14 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.97

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=0.010186464).
• BP6: Variant 17-80065575-G-A is Benign according to our data. Variant chr17-80065575-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80065575-G-A is described in Lovd as [Likely_benign]. Variant chr17-80065575-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00642 (977/152208) while in subpopulation AFR AF= 0.0225 (935/41554). AF 95% confidence interval is 0.0213. There are 10 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.1531G>A	p.Glu511Lys	missense_variant	10/20	ENST00000397545.9
LOC124904074	XR_007065931.1	n.305+5657C>T		intron_variant, non_coding_transcript_variant
CCDC40	NM_001243342.2	c.1531G>A	p.Glu511Lys	missense_variant	10/18
CCDC40	NM_001330508.2	c.1531G>A	p.Glu511Lys	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.1531G>A	p.Glu511Lys	missense_variant	10/20	5	NM_017950.4	P2
	ENST00000695611.1	n.313+5657C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 972 AN: 152090 Hom.: 10 Cov.: 29

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00155 AC: 385 AN: 247998 Hom.: 4 AF XY: 0.00106 AC XY: 143 AN XY: 135030

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.000783

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000637 AC: 930 AN: 1460656 Hom.: 14 Cov.: 32 AF XY: 0.000557 AC XY: 405 AN XY: 726650

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00642 AC: 977 AN: 152208 Hom.: 10 Cov.: 29 AF XY: 0.00601 AC XY: 447 AN XY: 74410

Gnomad4 AFR AF: 0.0225

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000235 Hom.: 1

Bravo AF: 0.00740

ESP6500AA AF: 0.0240 AC: 102

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00196 AC: 237

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu511Lys in exon 10 of CCDC40: This variant is not expected to have clinical si gnificance because it has been identified in 2.4% (102/4244) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs59978698). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

Primary ciliary dyskinesia 15 Benign:1

Likely benign, 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 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	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;T
Sift4G	Benign	0.066	T;T;D
Polyphen		1.0	.;D;.
Vest4		0.73
MVP		0.71
MPC		0.76
ClinPred		0.047	T
GERP RS		5.1
Varity_R		0.52
gMVP		0.35

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: rs59978698; hg19: chr17-78039374; COSMIC: COSV53898812;