NM_017950.4:c.677-4C>G

Variant names:

• chr17-80048579-C-G
• rs2289530
• NM_017950.4:c.677-4C>G

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.677-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,611,000 control chromosomes in the GnomAD database, including 47,727 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3588 hom., cov: 31)
  • Exomes 𝑓: 0.24 (44139 hom.)
• Consequence: CCDC40 NM_017950.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001481
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.87
• Publications: 13 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: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, 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 (BayesDel_noAF=-0.95).
• BP6: Variant 17-80048579-C-G is Benign according to our data. Variant chr17-80048579-C-G is described in ClinVar as Benign. ClinVar VariationId is 162846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.361 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.677-4C>G		splice_region intron	N/A	NP_060420.2
	CCDC40	NM_001243342.2		c.677-4C>G		splice_region intron	N/A	NP_001230271.1
	CCDC40	NM_001330508.2		c.677-4C>G		splice_region intron	N/A	NP_001317437.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.677-4C>G		splice_region intron	N/A	ENSP00000380679.4
	CCDC40	ENST00000374876.4	TSL:1	c.677-4C>G		splice_region intron	N/A	ENSP00000364010.4
	CCDC40	ENST00000574799.5	TSL:1	n.210C>G		non_coding_transcript_exon	Exon 1 of 16

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29788 AN: 152026 Hom.: 3583 Cov.: 31

Gnomad AFR AF: 0.0545

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.238 AC: 58601 AN: 245724 AF XY: 0.235

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.396

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.242 AC: 352656 AN: 1458856 Hom.: 44139 Cov.: 32 AF XY: 0.241 AC XY: 174974 AN XY: 725898

African (AFR) AF: 0.0423 AC: 1416 AN: 33444

American (AMR) AF: 0.303 AC: 13550 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 4807 AN: 26120

East Asian (EAS) AF: 0.327 AC: 12958 AN: 39650

South Asian (SAS) AF: 0.208 AC: 17901 AN: 86162

European-Finnish (FIN) AF: 0.220 AC: 11697 AN: 53092

Middle Eastern (MID) AF: 0.169 AC: 933 AN: 5512

European-Non Finnish (NFE) AF: 0.248 AC: 275592 AN: 1109988

Other (OTH) AF: 0.229 AC: 13802 AN: 60236

GnomAD4 genome AF: 0.196 AC: 29808 AN: 152144 Hom.: 3588 Cov.: 31 AF XY: 0.199 AC XY: 14798 AN XY: 74374

African (AFR) AF: 0.0544 AC: 2260 AN: 41536

American (AMR) AF: 0.293 AC: 4476 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3470

East Asian (EAS) AF: 0.375 AC: 1933 AN: 5158

South Asian (SAS) AF: 0.211 AC: 1016 AN: 4818

European-Finnish (FIN) AF: 0.218 AC: 2313 AN: 10602

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16473 AN: 67962

Other (OTH) AF: 0.203 AC: 427 AN: 2108

Alfa AF: 0.172 Hom.: 621

Bravo AF: 0.194

EpiCase AF: 0.238

EpiControl AF: 0.234

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.041
DANN	Benign	0.35
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs2289530; hg19: chr17-78022378; COSMIC: COSV53896456; COSMIC: COSV53896456;