rs765319797

Variant names:

• chr17-80036681-G-A
• rs765319797
• NM_017950.4:c.19G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80036681-G-A
• chr17-80036681-G-C
• chr17-80036681-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017950.4(CCDC40):​c.19G>A​(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000053 (0 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.93
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.063898414).

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.19G>A	p.Ala7Thr	missense	Exon 1 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.19G>A	p.Ala7Thr	missense	Exon 1 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.19G>A	p.Ala7Thr	missense	Exon 1 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.19G>A	p.Ala7Thr	missense	Exon 1 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.19G>A	p.Ala7Thr	missense	Exon 1 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000897784.1		c.19G>A	p.Ala7Thr	missense	Exon 1 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000535 AC: 7 AN: 1308554 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 643192

African (AFR) AF: 0.000254 AC: 7 AN: 27582

American (AMR) AF: 0.00 AC: 0 AN: 26804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22764

East Asian (EAS) AF: 0.00 AC: 0 AN: 29944

South Asian (SAS) AF: 0.00 AC: 0 AN: 70094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1040392

Other (OTH) AF: 0.00 AC: 0 AN: 54056

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151958 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74226

African (AFR) AF: 0.0000968 AC: 4 AN: 41330

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.56
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-2.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.055
Sift	Benign	0.24	T
Sift4G	Benign	0.45	T
Polyphen		0.34	B
Vest4		0.097
MutPred		0.34		Gain of phosphorylation at A7 (P = 0.0068)
MVP		0.055
MPC		0.17
ClinPred		0.14	T
GERP RS		-3.3
PromoterAI		-0.0052	Neutral
Varity_R		0.025
gMVP		0.027
Mutation Taster		=96/4	polymorphism

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: rs765319797; hg19: chr17-78010480;