17-80050247-A-C

Position:

• chr17-80050247-A-C

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.1123A>C​(p.Lys375Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,590,146 control chromosomes in the GnomAD database, including 31 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (15 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0400

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]

CCDC40 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034354925).
• BP6: Variant 17-80050247-A-C is Benign according to our data. Variant chr17-80050247-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 241230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80050247-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0086 (1309/152286) while in subpopulation AFR AF= 0.0293 (1217/41558). AF 95% confidence interval is 0.0279. There are 16 homozygotes in gnomad4. There are 599 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.1123A>C	p.Lys375Gln	missense_variant	7/20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.1123A>C	p.Lys375Gln	missense_variant	7/18		NP_001230271.1
CCDC40	NM_001330508.2	c.1123A>C	p.Lys375Gln	missense_variant	7/11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.1123A>C	p.Lys375Gln	missense_variant	7/20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.00856 AC: 1303 AN: 152168 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00218 AC: 446 AN: 204454 Hom.: 2 AF XY: 0.00159 AC XY: 178 AN XY: 111918

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000260

Gnomad OTH exome AF: 0.000766

GnomAD4 exome AF: 0.000979 AC: 1407 AN: 1437860 Hom.: 15 Cov.: 34 AF XY: 0.000876 AC XY: 625 AN XY: 713772

Gnomad4 AFR exome AF: 0.0313

Gnomad4 AMR exome AF: 0.00196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000598

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00860 AC: 1309 AN: 152286 Hom.: 16 Cov.: 32 AF XY: 0.00804 AC XY: 599 AN XY: 74472

Gnomad4 AFR AF: 0.0293

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00144 Hom.: 2

Bravo AF: 0.00996

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0151 AC: 63

ESP6500EA AF: 0.000476 AC: 4

ExAC AF: 0.00231 AC: 276

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Lys375Gln in exon 7 of CCDC40: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (63/4160) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs61734951). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 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. -

Primary ciliary dyskinesia 15 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.0
DANN	Benign	0.63
DEOGEN2	Benign	0.059	.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.67	T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.014, 0.58	.;B;.;P
Vest4		0.21
MVP		0.095
MPC		0.20
ClinPred		0.012	T
GERP RS		-3.3
Varity_R		0.076
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: rs61734951; hg19: chr17-78024046;