rs61740509

Variant names:

• chr17-80099686-G-A
• rs61740509
• NM_017950.4:c.3340G>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.3340G>A​(p.Val1114Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,613,850 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (198 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.759
• Publications: 10 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=0.002135545).
• BP6: Variant 17-80099686-G-A is Benign according to our data. Variant chr17-80099686-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95880.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0782 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.3340G>A	p.Val1114Met	missense	Exon 20 of 20	NP_060420.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.3340G>A	p.Val1114Met	missense	Exon 20 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.2877G>A		non_coding_transcript_exon	Exon 16 of 16
	CCDC40	ENST00000897784.1		c.3532G>A	p.Val1178Met	missense	Exon 21 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1277 AN: 152152 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0148 AC: 3696 AN: 249158 AF XY: 0.0115

Gnomad AFR exome AF: 0.000841

Gnomad AMR exome AF: 0.0832

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00941

GnomAD4 exome AF: 0.00574 AC: 8391 AN: 1461580 Hom.: 198 Cov.: 36 AF XY: 0.00536 AC XY: 3895 AN XY: 727074

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.0804 AC: 3594 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00508 AC: 438 AN: 86258

European-Finnish (FIN) AF: 0.0119 AC: 632 AN: 53122

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00301 AC: 3350 AN: 1112002

Other (OTH) AF: 0.00550 AC: 332 AN: 60392

GnomAD4 genome AF: 0.00840 AC: 1279 AN: 152270 Hom.: 20 Cov.: 32 AF XY: 0.0101 AC XY: 755 AN XY: 74452

African (AFR) AF: 0.00142 AC: 59 AN: 41550

American (AMR) AF: 0.0508 AC: 778 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4826

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68014

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00421 Hom.: 15

Bravo AF: 0.0112

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00121 AC: 5

ESP6500EA AF: 0.00238 AC: 20

ExAC AF: 0.0118 AC: 1433

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	not provided (2)
-	-	1	Glycogen storage disease, type II (1)
-	-	1	Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.76
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.022	D
Polyphen		0.99	D
Vest4		0.14
MPC		0.60
ClinPred		0.012	T
GERP RS		2.4
Varity_R		0.074
gMVP		0.20
Mutation Taster		=98/2	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: rs61740509; hg19: chr17-78073485; COSMIC: COSV56409883; COSMIC: COSV56409883;