rs2143550064

Variant names:

• chr17-80036665-G-A
• rs2143550064
• NM_017950.4:c.3G>A

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.3G>A​(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 0.000000763 in 1,310,312 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: 7.6e-7 (0 hom.)
• Consequence: CCDC40 NM_017950.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• 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: 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: 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.3G>A	p.Met1?	start_lost	Exon 1 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 18		NP_001230271.1
CCDC40	NM_001330508.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.3G>A	p.Met1?	start_lost	Exon 1 of 20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1310312 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 644206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27748

American (AMR) AF: 0.0000377 AC: 1 AN: 26548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22654

East Asian (EAS) AF: 0.00 AC: 0 AN: 30284

South Asian (SAS) AF: 0.00 AC: 0 AN: 69904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041888

Other (OTH) AF: 0.00 AC: 0 AN: 54116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 15 Uncertain:1

Mar 22, 2022

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alterante start codon . It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	.;T;.;.
Eigen	Benign	0.0062
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.74	T
PhyloP100		1.3
PROVEAN	Benign	-0.89	N;N;N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.81, 0.88	.;P;.;P
Vest4		0.76
MutPred		0.98		Loss of catalytic residue at M1 (P = 0.3434);Loss of catalytic residue at M1 (P = 0.3434);Loss of catalytic residue at M1 (P = 0.3434);Loss of catalytic residue at M1 (P = 0.3434);
MVP		0.54
ClinPred		0.84	D
GERP RS		1.8
PromoterAI		-0.70	Under-expression
Varity_R		0.91
gMVP		0.22
Mutation Taster		=62/138	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: rs2143550064; hg19: chr17-78010464;