rs1555889343

chr17-80038176-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_017950.4(CCDC40):c.83A>G(p.Glu28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.122

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.100384355).
• BP6: Variant 17-80038176-A-G is Benign according to our data. Variant chr17-80038176-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 505068.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC40	NM_017950.4	c.83A>G	p.Glu28Gly	missense_variant	2/20	ENST00000397545.9
CCDC40	NM_001243342.2	c.83A>G	p.Glu28Gly	missense_variant	2/18
CCDC40	NM_001330508.2	c.83A>G	p.Glu28Gly	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC40	ENST00000397545.9	c.83A>G	p.Glu28Gly	missense_variant	2/20	5	NM_017950.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 07, 2016

p.Glu28Gly of CCDC40: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, four mammals have a glycine (Gly) at this position despite high nearby amino acid con servation. In addition, computational prediction tools do not suggest a high lik elihood of impact to the protein. This variant was absent from large population studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	6.3
Dann	Uncertain	0.99
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.45	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.55	N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.055
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.052	T;D;D;D
Polyphen		0.18, 0.87	.;B;.;P
Vest4		0.18
MutPred		0.17		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.52
MPC		0.24
ClinPred		0.25	T
GERP RS		2.2
Varity_R		0.058
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555889343; hg19: chr17-78011975;