NM_017950.4:c.3210A>G

Variant names:

• chr17-80099556-A-G
• rs56407805
• NM_017950.4:c.3210A>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.3210A>G​(p.Thr1070Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,611,218 control chromosomes in the GnomAD database, including 73,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10236 hom., cov: 31)
  • Exomes 𝑓: 0.29 (63158 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.62
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-80099556-A-G is Benign according to our data. Variant chr17-80099556-A-G is described in ClinVar as Benign. ClinVar VariationId is 162852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.506 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.3210A>G	p.Thr1070Thr	synonymous	Exon 20 of 20	NP_060420.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.3210A>G	p.Thr1070Thr	synonymous	Exon 20 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.2747A>G		non_coding_transcript_exon	Exon 16 of 16
	CCDC40	ENST00000897784.1		c.3402A>G	p.Thr1134Thr	synonymous	Exon 21 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53166 AN: 151880 Hom.: 10219 Cov.: 31

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.327

GnomAD2 exomes AF: 0.303 AC: 74940 AN: 247662 AF XY: 0.305

Gnomad AFR exome AF: 0.517

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.409

Gnomad FIN exome AF: 0.328

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.309

GnomAD4 exome AF: 0.288 AC: 420850 AN: 1459220 Hom.: 63158 Cov.: 36 AF XY: 0.290 AC XY: 210357 AN XY: 726066

African (AFR) AF: 0.519 AC: 17388 AN: 33474

American (AMR) AF: 0.171 AC: 7643 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6997 AN: 26136

East Asian (EAS) AF: 0.453 AC: 17986 AN: 39696

South Asian (SAS) AF: 0.325 AC: 28029 AN: 86250

European-Finnish (FIN) AF: 0.339 AC: 17319 AN: 51116

Middle Eastern (MID) AF: 0.302 AC: 1738 AN: 5760

European-Non Finnish (NFE) AF: 0.275 AC: 305216 AN: 1111700

Other (OTH) AF: 0.307 AC: 18534 AN: 60364

GnomAD4 genome AF: 0.350 AC: 53224 AN: 151998 Hom.: 10236 Cov.: 31 AF XY: 0.349 AC XY: 25909 AN XY: 74302

African (AFR) AF: 0.511 AC: 21185 AN: 41432

American (AMR) AF: 0.214 AC: 3274 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 891 AN: 3472

East Asian (EAS) AF: 0.425 AC: 2191 AN: 5152

South Asian (SAS) AF: 0.327 AC: 1575 AN: 4816

European-Finnish (FIN) AF: 0.334 AC: 3528 AN: 10578

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.287 AC: 19473 AN: 67966

Other (OTH) AF: 0.331 AC: 697 AN: 2106

Alfa AF: 0.307 Hom.: 4512

Bravo AF: 0.348

Asia WGS AF: 0.388 AC: 1351 AN: 3478

EpiCase AF: 0.279

EpiControl AF: 0.276

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Primary ciliary dyskinesia (3)
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia 15 (2)
-	-	1	Glycogen storage disease, type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.063
DANN	Benign	0.56
PhyloP100		-2.6
Mutation Taster		=100/0	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: rs56407805; hg19: chr17-78073355; COSMIC: COSV56410864; COSMIC: COSV56410864;