17-80081959-T-G

Variant names:

• chr17-80081959-T-G
• rs35578653
• NM_017950.4:c.1890T>G

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.1890T>G​(p.Ala630Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 1,613,186 control chromosomes in the GnomAD database, including 212,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20864 hom., cov: 30)
  • Exomes 𝑓: 0.51 (191388 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.81
• 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: ClinGen, PanelApp Australia, Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autoimmune disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-80081959-T-G is Benign according to our data. Variant chr17-80081959-T-G is described in ClinVar as Benign. ClinVar VariationId is 162850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.582 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.1890T>G	p.Ala630Ala	synonymous	Exon 12 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.1890T>G	p.Ala630Ala	synonymous	Exon 12 of 18	NP_001230271.1	Q4G0X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.1890T>G	p.Ala630Ala	synonymous	Exon 12 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.1427T>G		non_coding_transcript_exon	Exon 8 of 16
	CCDC40	ENST00000897784.1		c.1890T>G	p.Ala630Ala	synonymous	Exon 12 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78617 AN: 151548 Hom.: 20865 Cov.: 30

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.650

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.548

GnomAD2 exomes AF: 0.481 AC: 119687 AN: 248586 AF XY: 0.487

Gnomad AFR exome AF: 0.589

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.603

Gnomad EAS exome AF: 0.272

Gnomad FIN exome AF: 0.489

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.508 AC: 743079 AN: 1461518 Hom.: 191388 Cov.: 45 AF XY: 0.508 AC XY: 369258 AN XY: 727056

African (AFR) AF: 0.595 AC: 19909 AN: 33480

American (AMR) AF: 0.392 AC: 17511 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 15764 AN: 26132

East Asian (EAS) AF: 0.310 AC: 12300 AN: 39694

South Asian (SAS) AF: 0.453 AC: 39072 AN: 86238

European-Finnish (FIN) AF: 0.490 AC: 26169 AN: 53398

Middle Eastern (MID) AF: 0.630 AC: 3635 AN: 5768

European-Non Finnish (NFE) AF: 0.519 AC: 577342 AN: 1111726

Other (OTH) AF: 0.520 AC: 31377 AN: 60388

GnomAD4 genome AF: 0.519 AC: 78647 AN: 151668 Hom.: 20864 Cov.: 30 AF XY: 0.512 AC XY: 37967 AN XY: 74106

African (AFR) AF: 0.588 AC: 24353 AN: 41396

American (AMR) AF: 0.428 AC: 6539 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.607 AC: 2108 AN: 3470

East Asian (EAS) AF: 0.279 AC: 1402 AN: 5032

South Asian (SAS) AF: 0.430 AC: 2067 AN: 4812

European-Finnish (FIN) AF: 0.486 AC: 5135 AN: 10556

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.522 AC: 35412 AN: 67830

Other (OTH) AF: 0.543 AC: 1144 AN: 2106

Alfa AF: 0.513 Hom.: 16445

Bravo AF: 0.518

Asia WGS AF: 0.339 AC: 1184 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.30
DANN	Benign	0.34
PhyloP100		-2.8
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: rs35578653; hg19: chr17-78055758; COSMIC: COSV66474806;