chr17-80040222-G-A

Variant names:

• chr17-80040222-G-A
• rs74000351
• NM_017950.4:c.504G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017950.4(CCDC40):​c.504G>A​(p.Pro168Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,613,952 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P168P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (176 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (133 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.97
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autoimmune disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 17-80040222-G-A is Benign according to our data. Variant chr17-80040222-G-A is described in ClinVar as Benign. ClinVar VariationId is 226494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0844 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017950.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.504G>A	p.Pro168Pro	synonymous	Exon 3 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.504G>A	p.Pro168Pro	synonymous	Exon 3 of 18	NP_001230271.1
	CCDC40	NM_001330508.2		c.504G>A	p.Pro168Pro	synonymous	Exon 3 of 11	NP_001317437.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.504G>A	p.Pro168Pro	synonymous	Exon 3 of 20	ENSP00000380679.4
	CCDC40	ENST00000374876.4	TSL:1	c.504G>A	p.Pro168Pro	synonymous	Exon 3 of 9	ENSP00000364010.4
	CCDC40	ENST00000897784.1		c.504G>A	p.Pro168Pro	synonymous	Exon 3 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3903 AN: 152174 Hom.: 176 Cov.: 32

Gnomad AFR AF: 0.0867

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.00735 AC: 1824 AN: 248174 AF XY: 0.00580

Gnomad AFR exome AF: 0.0921

Gnomad AMR exome AF: 0.00455

Gnomad ASJ exome AF: 0.00858

Gnomad EAS exome AF: 0.00312

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000606

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00304 AC: 4440 AN: 1461660 Hom.: 133 Cov.: 33 AF XY: 0.00274 AC XY: 1990 AN XY: 727134

African (AFR) AF: 0.0892 AC: 2985 AN: 33464

American (AMR) AF: 0.00544 AC: 243 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 196 AN: 26124

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39698

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.0164 AC: 94 AN: 5718

European-Non Finnish (NFE) AF: 0.000339 AC: 377 AN: 1111938

Other (OTH) AF: 0.00697 AC: 421 AN: 60378

GnomAD4 genome AF: 0.0257 AC: 3915 AN: 152292 Hom.: 176 Cov.: 32 AF XY: 0.0243 AC XY: 1807 AN XY: 74474

African (AFR) AF: 0.0868 AC: 3605 AN: 41536

American (AMR) AF: 0.0118 AC: 181 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5186

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68026

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.00935 Hom.: 36

Bravo AF: 0.0303

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	2	Primary ciliary dyskinesia 15 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74000351; hg19: chr17-78014021; COSMIC: COSV53899874; COSMIC: COSV53899874;