rs62000409

Variant names:

• chr17-80058637-G-A
• rs62000409
• NM_017950.4:c.1303G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80058637-G-A
• chr17-80058637-G-C

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.1303G>A​(p.Glu435Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00123 in 1,614,214 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E435E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0061 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (11 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.57
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0098976195).
• BP6: Variant 17-80058637-G-A is Benign according to our data. Variant chr17-80058637-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241233.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 = 0.00614 (935/152340) while in subpopulation AFR AF = 0.0209 (868/41588). AF 95% confidence interval is 0.0197. There are 14 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.1303G>A	p.Glu435Lys	missense	Exon 8 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.1303G>A	p.Glu435Lys	missense	Exon 8 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.1303G>A	p.Glu435Lys	missense	Exon 8 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.1303G>A	p.Glu435Lys	missense	Exon 8 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.1303G>A	p.Glu435Lys	missense	Exon 8 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000574799.5	TSL:1	n.840G>A		non_coding_transcript_exon	Exon 4 of 16

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 929 AN: 152222 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00145 AC: 363 AN: 249526 AF XY: 0.00100

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000718 AC: 1049 AN: 1461874 Hom.: 11 Cov.: 32 AF XY: 0.000642 AC XY: 467 AN XY: 727244

African (AFR) AF: 0.0229 AC: 768 AN: 33478

American (AMR) AF: 0.00161 AC: 72 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1112004

Other (OTH) AF: 0.00225 AC: 136 AN: 60394

GnomAD4 genome AF: 0.00614 AC: 935 AN: 152340 Hom.: 14 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74496

African (AFR) AF: 0.0209 AC: 868 AN: 41588

American (AMR) AF: 0.00301 AC: 46 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

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

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00191 Hom.: 10

Bravo AF: 0.00683

ESP6500AA AF: 0.0146 AC: 59

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00182 AC: 220

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Primary ciliary dyskinesia (2)
-	-	2	Primary ciliary dyskinesia 15 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.28
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.66
MVP		0.82
MPC		0.72
ClinPred		0.019	T
GERP RS		5.0
PromoterAI		-0.041	Neutral
Varity_R		0.25
gMVP		0.31
Mutation Taster		=93/7	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: rs62000409; hg19: chr17-78032436; COSMIC: COSV105835229; COSMIC: COSV105835229;