chr17-80036664-T-G

Variant names:

• chr17-80036664-T-G
• NM_017950.4:c.2T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_017950.4(CCDC40):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000153 in 1,308,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CCDC40 NM_017950.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• 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: 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 31 codons. Genomic position: 80038184. Lost 0.027 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.2T>G	p.Met1?	start_lost	Exon 1 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.2T>G	p.Met1?	start_lost	Exon 1 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.2T>G	p.Met1?	start_lost	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.2T>G	p.Met1?	start_lost	Exon 1 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000897784.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1308422 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 643358

African (AFR) AF: 0.00 AC: 0 AN: 27698

American (AMR) AF: 0.00 AC: 0 AN: 26420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22580

East Asian (EAS) AF: 0.00 AC: 0 AN: 30264

South Asian (SAS) AF: 0.00 AC: 0 AN: 69642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4646

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1041134

Other (OTH) AF: 0.00 AC: 0 AN: 53982

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.039	T
Eigen	Benign	0.013
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.67	T
PhyloP100		1.1
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.85
MutPred		0.98		Loss of catalytic residue at M1 (P = 0.0026)
MVP		0.67
ClinPred		0.70	D
GERP RS		1.8
PromoterAI		-0.70	Under-expression
Varity_R		0.96
gMVP		0.44
Mutation Taster		=61/139	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

hg19: chr17-78010463;