rs2289526

Variant names:

• chr17-80039860-G-A
• rs2289526
• NM_017950.4:c.142G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017950.4(CCDC40):​c.142G>A​(p.Gly48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.760
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08182576).

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.142G>A	p.Gly48Ser	missense	Exon 3 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.142G>A	p.Gly48Ser	missense	Exon 3 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.142G>A	p.Gly48Ser	missense	Exon 3 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.142G>A	p.Gly48Ser	missense	Exon 3 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.142G>A	p.Gly48Ser	missense	Exon 3 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000897784.1		c.142G>A	p.Gly48Ser	missense	Exon 3 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151904 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000364 AC: 9 AN: 247072 AF XY: 0.0000447

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44722

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

East Asian (EAS) AF: 0.00106 AC: 42 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111984

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151904 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74150

African (AFR) AF: 0.0000242 AC: 1 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15240

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000845 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000331 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia (2)
-	1	-	Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.76
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.070
Sift	Benign	0.055	T
Sift4G	Uncertain	0.059	T
Polyphen		0.013	B
Vest4		0.096
MutPred		0.23		Gain of phosphorylation at G48 (P = 0.0137)
MVP		0.44
MPC		0.17
ClinPred		0.035	T
GERP RS		2.4
Varity_R		0.031
gMVP		0.041
Mutation Taster		=96/4	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: rs2289526; hg19: chr17-78013659; COSMIC: COSV53900272; COSMIC: COSV53900272;