NM_017950.4:c.1889C>T

Variant names:

• chr17-80081958-C-T
• rs61749058
• NM_017950.4:c.1889C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017950.4(CCDC40):​c.1889C>T​(p.Ala630Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,613,548 control chromosomes in the GnomAD database, including 10,044 homozygotes. 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A630A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.085 (641 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9403 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.582
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018564463).
• BP6: Variant 17-80081958-C-T is Benign according to our data. Variant chr17-80081958-C-T is described in ClinVar as Benign. ClinVar VariationId is 162849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	NM_017950.4	MANE Select	c.1889C>T	p.Ala630Val	missense	Exon 12 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.1889C>T	p.Ala630Val	missense	Exon 12 of 18	NP_001230271.1	Q4G0X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.1889C>T	p.Ala630Val	missense	Exon 12 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.1426C>T		non_coding_transcript_exon	Exon 8 of 16
	CCDC40	ENST00000897784.1		c.1889C>T	p.Ala630Val	missense	Exon 12 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12977 AN: 151938 Hom.: 642 Cov.: 32

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.000588

Gnomad SAS AF: 0.0553

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.0823

GnomAD2 exomes AF: 0.0901 AC: 22430 AN: 248870 AF XY: 0.0934

Gnomad AFR exome AF: 0.0440

Gnomad AMR exome AF: 0.0470

Gnomad ASJ exome AF: 0.0973

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.109 AC: 158777 AN: 1461492 Hom.: 9403 Cov.: 32 AF XY: 0.108 AC XY: 78411 AN XY: 727040

African (AFR) AF: 0.0430 AC: 1438 AN: 33474

American (AMR) AF: 0.0487 AC: 2176 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0977 AC: 2552 AN: 26130

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39696

South Asian (SAS) AF: 0.0618 AC: 5332 AN: 86210

European-Finnish (FIN) AF: 0.141 AC: 7550 AN: 53406

Middle Eastern (MID) AF: 0.0865 AC: 499 AN: 5768

European-Non Finnish (NFE) AF: 0.120 AC: 133332 AN: 1111726

Other (OTH) AF: 0.0975 AC: 5885 AN: 60384

GnomAD4 genome AF: 0.0853 AC: 12976 AN: 152056 Hom.: 641 Cov.: 32 AF XY: 0.0844 AC XY: 6270 AN XY: 74310

African (AFR) AF: 0.0447 AC: 1858 AN: 41534

American (AMR) AF: 0.0584 AC: 893 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 338 AN: 3470

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5090

South Asian (SAS) AF: 0.0546 AC: 263 AN: 4820

European-Finnish (FIN) AF: 0.130 AC: 1379 AN: 10594

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7957 AN: 67938

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.107 Hom.: 1734

Bravo AF: 0.0793

ExAC AF: 0.0909 AC: 11014

Asia WGS AF: 0.0270 AC: 97 AN: 3478

EpiCase AF: 0.113

EpiControl AF: 0.119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.58
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.028
Sift	Benign	0.22	T
Sift4G	Benign	0.44	T
Polyphen		0.75	P
Vest4		0.12
MPC		0.18
ClinPred		0.010	T
GERP RS		0.23
Varity_R		0.041
gMVP		0.10
Mutation Taster		=97/3	polymorphism (auto)

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: rs61749058; hg19: chr17-78055757; COSMIC: COSV66476862;