rs74692882

Variant names:

• chr17-80050255-C-T
• rs74692882
• NM_017950.4:c.1131C>T

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.1131C>T​(p.Cys377Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,583,052 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (52 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.581
• Publications: 2 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

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

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000289689 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-80050255-C-T is Benign according to our data. Variant chr17-80050255-C-T is described in ClinVar as Benign. ClinVar VariationId is 226486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.581 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 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.1131C>T	p.Cys377Cys	synonymous	Exon 7 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.1131C>T	p.Cys377Cys	synonymous	Exon 7 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.1131C>T	p.Cys377Cys	synonymous	Exon 7 of 11	NP_001317437.1	Q4G0X9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.1131C>T	p.Cys377Cys	synonymous	Exon 7 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.1131C>T	p.Cys377Cys	synonymous	Exon 7 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000574799.5	TSL:1	n.668C>T		non_coding_transcript_exon	Exon 3 of 16

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2251 AN: 152160 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00351 AC: 675 AN: 192176 AF XY: 0.00253

Gnomad AFR exome AF: 0.0562

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00150 AC: 2145 AN: 1430774 Hom.: 52 Cov.: 34 AF XY: 0.00121 AC XY: 856 AN XY: 709618

African (AFR) AF: 0.0557 AC: 1817 AN: 32598

American (AMR) AF: 0.00252 AC: 100 AN: 39734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 37842

South Asian (SAS) AF: 0.000133 AC: 11 AN: 82906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50356

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4136

European-Non Finnish (NFE) AF: 0.0000364 AC: 40 AN: 1098456

Other (OTH) AF: 0.00287 AC: 170 AN: 59140

GnomAD4 genome AF: 0.0148 AC: 2251 AN: 152278 Hom.: 56 Cov.: 32 AF XY: 0.0146 AC XY: 1088 AN XY: 74444

African (AFR) AF: 0.0516 AC: 2146 AN: 41556

American (AMR) AF: 0.00484 AC: 74 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00742 Hom.: 16

Bravo AF: 0.0169

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

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)
-	-	1	Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.8
DANN	Benign	0.47
PhyloP100		-0.58
Mutation Taster		=87/13	polymorphism

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: rs74692882; hg19: chr17-78024054;