NM_017950.4:c.207G>C

Variant names:

• chr17-80039925-G-C
• rs2289527
• NM_017950.4:c.207G>C

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.207G>C​(p.Val69Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.982 in 1,613,522 control chromosomes in the GnomAD database, including 778,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V69V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.99 (73734 hom., cov: 28)
  • Exomes 𝑓: 0.98 (704889 hom.)
• Consequence: CCDC40 NM_017950.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.77
• Publications: 16 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 17-80039925-G-C is Benign according to our data. Variant chr17-80039925-G-C is described in ClinVar as Benign. ClinVar VariationId is 166807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.985 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.207G>C	p.Val69Val	synonymous	Exon 3 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.207G>C	p.Val69Val	synonymous	Exon 3 of 18	NP_001230271.1
	CCDC40	NM_001330508.2		c.207G>C	p.Val69Val	synonymous	Exon 3 of 11	NP_001317437.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.207G>C	p.Val69Val	synonymous	Exon 3 of 20	ENSP00000380679.4
	CCDC40	ENST00000374876.4	TSL:1	c.207G>C	p.Val69Val	synonymous	Exon 3 of 9	ENSP00000364010.4
	CCDC40	ENST00000897784.1		c.207G>C	p.Val69Val	synonymous	Exon 3 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.985 AC: 149504 AN: 151774 Hom.: 73676 Cov.: 28

Gnomad AFR AF: 0.993

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.988

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.905

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.979

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.991

GnomAD2 exomes AF: 0.970 AC: 239634 AN: 247120 AF XY: 0.969

Gnomad AFR exome AF: 0.994

Gnomad AMR exome AF: 0.965

Gnomad ASJ exome AF: 0.983

Gnomad EAS exome AF: 0.906

Gnomad FIN exome AF: 0.978

Gnomad NFE exome AF: 0.990

Gnomad OTH exome AF: 0.979

GnomAD4 exome AF: 0.982 AC: 1434859 AN: 1461630 Hom.: 704889 Cov.: 40 AF XY: 0.980 AC XY: 712602 AN XY: 727136

African (AFR) AF: 0.994 AC: 33288 AN: 33476

American (AMR) AF: 0.969 AC: 43332 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 25691 AN: 26136

East Asian (EAS) AF: 0.888 AC: 35266 AN: 39696

South Asian (SAS) AF: 0.915 AC: 78925 AN: 86252

European-Finnish (FIN) AF: 0.979 AC: 52297 AN: 53420

Middle Eastern (MID) AF: 0.992 AC: 5717 AN: 5766

European-Non Finnish (NFE) AF: 0.991 AC: 1101224 AN: 1111772

Other (OTH) AF: 0.979 AC: 59119 AN: 60390

GnomAD4 genome AF: 0.985 AC: 149621 AN: 151892 Hom.: 73734 Cov.: 28 AF XY: 0.983 AC XY: 72934 AN XY: 74206

African (AFR) AF: 0.993 AC: 41130 AN: 41404

American (AMR) AF: 0.988 AC: 15037 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.984 AC: 3417 AN: 3472

East Asian (EAS) AF: 0.905 AC: 4647 AN: 5134

South Asian (SAS) AF: 0.909 AC: 4369 AN: 4808

European-Finnish (FIN) AF: 0.979 AC: 10322 AN: 10542

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67405 AN: 68002

Other (OTH) AF: 0.991 AC: 2088 AN: 2108

Alfa AF: 0.989 Hom.: 18343

Bravo AF: 0.987

Asia WGS AF: 0.903 AC: 3142 AN: 3478

EpiCase AF: 0.993

EpiControl AF: 0.992

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-1.0
CADD	Benign	0.080
DANN	Benign	0.48
PhyloP100		-2.8
Mutation Taster		=6/94	disease causing

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: rs2289527; hg19: chr17-78013724; COSMIC: COSV108068138; COSMIC: COSV108068138;