rs117203086

Variant names:

• chr17-80086022-T-C
• rs117203086
• NM_017950.4:c.2255T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-80086022-T-C
• chr17-80086022-T-A
• chr17-80086022-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017950.4(CCDC40):​c.2255T>C​(p.Leu752Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0219 in 1,613,976 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (35 hom., cov: 32)
  • Exomes 𝑓: 0.022 (443 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.68
• Publications: 11 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008146107).
• BP6: Variant 17-80086022-T-C is Benign according to our data. Variant chr17-80086022-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.018 (2742/152222) while in subpopulation NFE AF = 0.0239 (1624/68018). AF 95% confidence interval is 0.0229. There are 35 homozygotes in GnomAd4. There are 1376 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR,AD gene

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.2255T>C	p.Leu752Pro	missense	Exon 14 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.2255T>C	p.Leu752Pro	missense	Exon 14 of 18	NP_001230271.1	Q4G0X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.2255T>C	p.Leu752Pro	missense	Exon 14 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.1792T>C		non_coding_transcript_exon	Exon 10 of 16
	CCDC40	ENST00000897784.1		c.2255T>C	p.Leu752Pro	missense	Exon 14 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2742 AN: 152104 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0185 AC: 4617 AN: 249478 AF XY: 0.0188

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.00964

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0458

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0223 AC: 32614 AN: 1461754 Hom.: 443 Cov.: 31 AF XY: 0.0219 AC XY: 15950 AN XY: 727174

African (AFR) AF: 0.00353 AC: 118 AN: 33472

American (AMR) AF: 0.00935 AC: 418 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0177 AC: 462 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0108 AC: 928 AN: 86254

European-Finnish (FIN) AF: 0.0423 AC: 2260 AN: 53404

Middle Eastern (MID) AF: 0.0227 AC: 130 AN: 5716

European-Non Finnish (NFE) AF: 0.0244 AC: 27185 AN: 1111972

Other (OTH) AF: 0.0184 AC: 1112 AN: 60378

GnomAD4 genome AF: 0.0180 AC: 2742 AN: 152222 Hom.: 35 Cov.: 32 AF XY: 0.0185 AC XY: 1376 AN XY: 74428

African (AFR) AF: 0.00448 AC: 186 AN: 41554

American (AMR) AF: 0.0128 AC: 195 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4830

European-Finnish (FIN) AF: 0.0521 AC: 552 AN: 10596

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0239 AC: 1624 AN: 68018

Other (OTH) AF: 0.0143 AC: 30 AN: 2104

Alfa AF: 0.0196 Hom.: 102

Bravo AF: 0.0149

TwinsUK AF: 0.0213 AC: 79

ALSPAC AF: 0.0254 AC: 98

ESP6500AA AF: 0.00475 AC: 18

ESP6500EA AF: 0.0247 AC: 203

ExAC AF: 0.0182 AC: 2194

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0239

EpiControl AF: 0.0235

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.16	T
Polyphen		0.50	P
Vest4		0.52
MPC		0.47
ClinPred		0.026	T
GERP RS		4.7
Varity_R		0.86
gMVP		0.86
Mutation Taster		=92/8	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: rs117203086; hg19: chr17-78059821; COSMIC: COSV107494436; COSMIC: COSV107494436;