rs61734950

Variant names:

• chr17-80058878-C-T
• rs61734950
• NM_017950.4:c.1338C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_017950.4(CCDC40):​c.1338C>T​(p.Leu446Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,056 control chromosomes in the GnomAD database, including 1,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (487 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (595 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.905
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-80058878-C-T is Benign according to our data. Variant chr17-80058878-C-T is described in ClinVar as Benign. ClinVar VariationId is 162848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.905 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 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.1338C>T	p.Leu446Leu	synonymous	Exon 9 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.1338C>T	p.Leu446Leu	synonymous	Exon 9 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.1338C>T	p.Leu446Leu	synonymous	Exon 9 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.1338C>T	p.Leu446Leu	synonymous	Exon 9 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.1317+227C>T		intron	N/A	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000574799.5	TSL:1	n.875C>T		non_coding_transcript_exon	Exon 5 of 16

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6705 AN: 152050 Hom.: 480 Cov.: 32

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0315

GnomAD2 exomes AF: 0.0176 AC: 4403 AN: 249580 AF XY: 0.0172

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.00724

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00808

GnomAD4 exome AF: 0.00763 AC: 11155 AN: 1461888 Hom.: 595 Cov.: 32 AF XY: 0.00839 AC XY: 6101 AN XY: 727248

African (AFR) AF: 0.153 AC: 5109 AN: 33478

American (AMR) AF: 0.00812 AC: 363 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0500 AC: 4315 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00884 AC: 51 AN: 5768

European-Non Finnish (NFE) AF: 0.000388 AC: 432 AN: 1112010

Other (OTH) AF: 0.0144 AC: 867 AN: 60394

GnomAD4 genome AF: 0.0443 AC: 6745 AN: 152168 Hom.: 487 Cov.: 32 AF XY: 0.0437 AC XY: 3249 AN XY: 74416

African (AFR) AF: 0.149 AC: 6180 AN: 41482

American (AMR) AF: 0.0127 AC: 194 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5168

South Asian (SAS) AF: 0.0524 AC: 253 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68004

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0190 Hom.: 170

Bravo AF: 0.0488

Asia WGS AF: 0.0440 AC: 153 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.2
DANN	Benign	0.50
PhyloP100		-0.91
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	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: rs61734950; hg19: chr17-78032677;