chr17-80097217-G-A

Variant names:

• chr17-80097217-G-A
• rs74000392
• NM_017950.4:c.3022-28G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017950.4(CCDC40):​c.3022-28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,222 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (96 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (225 hom.)
• Consequence: CCDC40 NM_017950.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.587
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-80097217-G-A is Benign according to our data. Variant chr17-80097217-G-A is described in ClinVar as Benign. ClinVar VariationId is 260967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0617 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.3022-28G>A		intron	N/A	NP_060420.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.3022-28G>A		intron	N/A	ENSP00000380679.4
	CCDC40	ENST00000574799.5	TSL:1	n.2559-28G>A		intron	N/A
	CCDC40	ENST00000897784.1		c.3214-28G>A		intron	N/A	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3613 AN: 152170 Hom.: 95 Cov.: 33

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0149 AC: 3722 AN: 249008 AF XY: 0.0148

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0475

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.00542

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00971 AC: 14179 AN: 1460934 Hom.: 225 Cov.: 30 AF XY: 0.0101 AC XY: 7333 AN XY: 726832

African (AFR) AF: 0.0671 AC: 2244 AN: 33450

American (AMR) AF: 0.00572 AC: 256 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26134

East Asian (EAS) AF: 0.0384 AC: 1524 AN: 39692

South Asian (SAS) AF: 0.0295 AC: 2548 AN: 86238

European-Finnish (FIN) AF: 0.000983 AC: 52 AN: 52910

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5764

European-Non Finnish (NFE) AF: 0.00586 AC: 6518 AN: 1111672

Other (OTH) AF: 0.0145 AC: 875 AN: 60352

GnomAD4 genome AF: 0.0238 AC: 3619 AN: 152288 Hom.: 96 Cov.: 33 AF XY: 0.0235 AC XY: 1752 AN XY: 74466

African (AFR) AF: 0.0637 AC: 2648 AN: 41554

American (AMR) AF: 0.00830 AC: 127 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.0514 AC: 267 AN: 5192

South Asian (SAS) AF: 0.0300 AC: 145 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 68002

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.00483 Hom.: 2

Bravo AF: 0.0265

Asia WGS AF: 0.0450 AC: 159 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.78
PhyloP100		-0.59
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: rs74000392; hg19: chr17-78071016;