rs2885349

Variant names:

• chr17-80040225-G-A
• rs2885349
• NM_017950.4:c.507G>A
• CCDC40 p.Ser169Ser

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.507G>A​(p.Ser169Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,613,862 control chromosomes in the GnomAD database, including 1,261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (632 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (629 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.70
• 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• 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=-0.85).
• BP6: Variant 17-80040225-G-A is Benign according to our data. Variant chr17-80040225-G-A is described in ClinVar as Benign. ClinVar VariationId is 162845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 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.507G>A	p.Ser169Ser	synonymous	Exon 3 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.507G>A	p.Ser169Ser	synonymous	Exon 3 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.507G>A	p.Ser169Ser	synonymous	Exon 3 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.507G>A	p.Ser169Ser	synonymous	Exon 3 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.507G>A	p.Ser169Ser	synonymous	Exon 3 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000897784.1		c.507G>A	p.Ser169Ser	synonymous	Exon 3 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.0501 AC: 7629 AN: 152160 Hom.: 623 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0359

GnomAD2 exomes AF: 0.0187 AC: 4643 AN: 247948 AF XY: 0.0173

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00838

Gnomad EAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00993

GnomAD4 exome AF: 0.00824 AC: 12050 AN: 1461584 Hom.: 629 Cov.: 33 AF XY: 0.00869 AC XY: 6316 AN XY: 727082

African (AFR) AF: 0.171 AC: 5728 AN: 33470

American (AMR) AF: 0.0116 AC: 519 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00697 AC: 182 AN: 26124

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39692

South Asian (SAS) AF: 0.0390 AC: 3362 AN: 86194

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53392

Middle Eastern (MID) AF: 0.0165 AC: 94 AN: 5694

European-Non Finnish (NFE) AF: 0.000962 AC: 1070 AN: 1111940

Other (OTH) AF: 0.0170 AC: 1024 AN: 60372

GnomAD4 genome AF: 0.0504 AC: 7677 AN: 152278 Hom.: 632 Cov.: 32 AF XY: 0.0490 AC XY: 3647 AN XY: 74474

African (AFR) AF: 0.168 AC: 6983 AN: 41532

American (AMR) AF: 0.0183 AC: 280 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5190

South Asian (SAS) AF: 0.0412 AC: 199 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00134 AC: 91 AN: 68028

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.0215 Hom.: 154

Bravo AF: 0.0558

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

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)
-	-	1	Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.96
DANN	Benign	0.44
PhyloP100		-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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2885349;

hg19: chr17-78014024;