rs61749025

Variant names:

• chr17-80087765-C-T
• rs61749025
• NM_017950.4:c.2608C>T

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.2608C>T​(p.Arg870Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,006 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R870H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (12 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.05
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061118007).
• BP6: Variant 17-80087765-C-T is Benign according to our data. Variant chr17-80087765-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0071 (1081/152284) while in subpopulation AFR AF = 0.0248 (1032/41550). AF 95% confidence interval is 0.0236. There are 11 homozygotes in GnomAd4. There are 522 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.2608C>T	p.Arg870Cys	missense	Exon 15 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.2608C>T	p.Arg870Cys	missense	Exon 15 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.2608C>T	p.Arg870Cys	missense	Exon 15 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.2145C>T		non_coding_transcript_exon	Exon 11 of 16
	CCDC40	ENST00000897784.1		c.2608C>T	p.Arg870Cys	missense	Exon 15 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1080 AN: 152166 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00177 AC: 442 AN: 249450 AF XY: 0.00140

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000655 AC: 957 AN: 1461722 Hom.: 12 Cov.: 33 AF XY: 0.000542 AC XY: 394 AN XY: 727180

African (AFR) AF: 0.0240 AC: 804 AN: 33474

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5752

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111902

Other (OTH) AF: 0.00113 AC: 68 AN: 60382

GnomAD4 genome AF: 0.00710 AC: 1081 AN: 152284 Hom.: 11 Cov.: 32 AF XY: 0.00701 AC XY: 522 AN XY: 74482

African (AFR) AF: 0.0248 AC: 1032 AN: 41550

American (AMR) AF: 0.00196 AC: 30 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00239 Hom.: 4

Bravo AF: 0.00758

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0190 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	2	Primary ciliary dyskinesia 15 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.1
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.19
Sift	Benign	0.055	T
Sift4G	Benign	0.070	T
Polyphen		0.73	P
Vest4		0.43
MVP		0.53
MPC		0.31
ClinPred		0.045	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.15
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs61749025; hg19: chr17-78061564; COSMIC: COSV99059064; COSMIC: COSV99059064;