NM_017950.4:c.637G>C

Variant names:

• chr17-80047363-G-C
• rs372360189
• NM_017950.4:c.637G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017950.4(CCDC40):​c.637G>C​(p.Glu213Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,328 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E213K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.700
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06269956).

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.637G>C	p.Glu213Gln	missense	Exon 4 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.637G>C	p.Glu213Gln	missense	Exon 4 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.637G>C	p.Glu213Gln	missense	Exon 4 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.637G>C	p.Glu213Gln	missense	Exon 4 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.637G>C	p.Glu213Gln	missense	Exon 4 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000897784.1		c.637G>C	p.Glu213Gln	missense	Exon 4 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247794 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461328 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726942

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000447 AC: 2 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.069
DANN	Benign	0.74
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.70
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.054
Sift	Benign	0.19	T
Sift4G	Benign	0.26	T
Polyphen		0.63	P
Vest4		0.11
MutPred		0.10		Loss of stability (P = 0.1478)
MVP		0.061
MPC		0.26
ClinPred		0.16	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.097
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs372360189; hg19: chr17-78021162;