NM_017950.4:c.873C>T

Variant names:

• chr17-80049923-C-T
• rs2289531
• NM_017950.4:c.873C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017950.4(CCDC40):​c.873C>T​(p.Phe291Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0916 in 1,613,484 control chromosomes in the GnomAD database, including 7,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (835 hom., cov: 31)
  • Exomes 𝑓: 0.091 (6703 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.21
• Publications: 17 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 17-80049923-C-T is Benign according to our data. Variant chr17-80049923-C-T is described in ClinVar as Benign. ClinVar VariationId is 178708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.153 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.873C>T	p.Phe291Phe	synonymous	Exon 6 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.873C>T	p.Phe291Phe	synonymous	Exon 6 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.873C>T	p.Phe291Phe	synonymous	Exon 6 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.873C>T	p.Phe291Phe	synonymous	Exon 6 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.873C>T	p.Phe291Phe	synonymous	Exon 6 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000574799.5	TSL:1	n.410C>T		non_coding_transcript_exon	Exon 2 of 16

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15268 AN: 151974 Hom.: 837 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0651

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.0991 AC: 24721 AN: 249498 AF XY: 0.102

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.0883

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0907 AC: 132589 AN: 1461390 Hom.: 6703 Cov.: 33 AF XY: 0.0924 AC XY: 67204 AN XY: 727016

African (AFR) AF: 0.115 AC: 3859 AN: 33478

American (AMR) AF: 0.0563 AC: 2519 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3405 AN: 26134

East Asian (EAS) AF: 0.182 AC: 7206 AN: 39690

South Asian (SAS) AF: 0.123 AC: 10632 AN: 86242

European-Finnish (FIN) AF: 0.110 AC: 5878 AN: 53416

Middle Eastern (MID) AF: 0.144 AC: 829 AN: 5764

European-Non Finnish (NFE) AF: 0.0830 AC: 92283 AN: 1111566

Other (OTH) AF: 0.0990 AC: 5978 AN: 60378

GnomAD4 genome AF: 0.100 AC: 15264 AN: 152094 Hom.: 835 Cov.: 31 AF XY: 0.102 AC XY: 7574 AN XY: 74328

African (AFR) AF: 0.114 AC: 4727 AN: 41494

American (AMR) AF: 0.0650 AC: 994 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 461 AN: 3464

East Asian (EAS) AF: 0.162 AC: 834 AN: 5144

South Asian (SAS) AF: 0.112 AC: 537 AN: 4812

European-Finnish (FIN) AF: 0.110 AC: 1163 AN: 10580

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6244 AN: 67998

Other (OTH) AF: 0.114 AC: 240 AN: 2112

Alfa AF: 0.0951 Hom.: 846

Bravo AF: 0.0962

Asia WGS AF: 0.118 AC: 410 AN: 3478

EpiCase AF: 0.0938

EpiControl AF: 0.0921

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)
-	-	2	Primary ciliary dyskinesia 15 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.3
DANN	Benign	0.70
PhyloP100		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2289531; hg19: chr17-78023722; COSMIC: COSV53898089; COSMIC: COSV53898089;