NM_017950.4:c.30-57G>A

Variant names:

• chr17-80038066-G-A
• rs146081939
• NM_017950.4:c.30-57G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017950.4(CCDC40):​c.30-57G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00758 in 1,183,138 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (36 hom.)
• Consequence: CCDC40 NM_017950.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0540
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-80038066-G-A is Benign according to our data. Variant chr17-80038066-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1213195.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00617 (939/152152) while in subpopulation NFE AF = 0.0089 (605/67998). AF 95% confidence interval is 0.00831. There are 8 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.30-57G>A		intron_variant	Intron 1 of 19	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.30-57G>A		intron_variant	Intron 1 of 17		NP_001230271.1
CCDC40	NM_001330508.2	c.30-57G>A		intron_variant	Intron 1 of 10		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.30-57G>A		intron_variant	Intron 1 of 19	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 938 AN: 152034 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00333

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00890

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00779 AC: 8032 AN: 1030986 Hom.: 36 Cov.: 13 AF XY: 0.00770 AC XY: 4088 AN XY: 531168

African (AFR) AF: 0.00153 AC: 38 AN: 24758

American (AMR) AF: 0.00212 AC: 90 AN: 42532

Ashkenazi Jewish (ASJ) AF: 0.000396 AC: 9 AN: 22734

East Asian (EAS) AF: 0.00 AC: 0 AN: 37212

South Asian (SAS) AF: 0.00503 AC: 383 AN: 76090

European-Finnish (FIN) AF: 0.0186 AC: 953 AN: 51212

Middle Eastern (MID) AF: 0.000423 AC: 2 AN: 4726

European-Non Finnish (NFE) AF: 0.00864 AC: 6275 AN: 726234

Other (OTH) AF: 0.00620 AC: 282 AN: 45488

GnomAD4 genome AF: 0.00617 AC: 939 AN: 152152 Hom.: 8 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74378

African (AFR) AF: 0.00166 AC: 69 AN: 41522

American (AMR) AF: 0.00203 AC: 31 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00354 AC: 17 AN: 4804

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00890 AC: 605 AN: 67998

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00631 Hom.: 2

Bravo AF: 0.00475

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 04, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.45
DANN	Benign	0.49
PhyloP100		-0.054
Mutation Taster		=100/0	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: rs146081939; hg19: chr17-78011865;