17-80036749-C-A

Variant names:

• chr17-80036749-C-A
• rs3752041
• NM_017950.4:c.29+58C>A

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.29+58C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,444,646 control chromosomes in the GnomAD database, including 42,343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3471 hom., cov: 31)
  • Exomes 𝑓: 0.24 (38872 hom.)
• Consequence: CCDC40 NM_017950.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.164
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-80036749-C-A is Benign according to our data. Variant chr17-80036749-C-A is described in ClinVar as [Benign]. Clinvar id is 1225552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.29+58C>A		intron_variant	Intron 1 of 19	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.29+58C>A		intron_variant	Intron 1 of 17		NP_001230271.1
CCDC40	NM_001330508.2	c.29+58C>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.29+58C>A		intron_variant	Intron 1 of 19	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29237 AN: 152040 Hom.: 3465 Cov.: 31

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.242 AC: 312137 AN: 1292490 Hom.: 38872 Cov.: 25 AF XY: 0.242 AC XY: 153276 AN XY: 634380

African (AFR) AF: 0.0425 AC: 1143 AN: 26888

American (AMR) AF: 0.309 AC: 8559 AN: 27708

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 4715 AN: 22854

East Asian (EAS) AF: 0.287 AC: 8377 AN: 29148

South Asian (SAS) AF: 0.211 AC: 14744 AN: 69812

European-Finnish (FIN) AF: 0.168 AC: 5189 AN: 30816

Middle Eastern (MID) AF: 0.196 AC: 1055 AN: 5374

European-Non Finnish (NFE) AF: 0.249 AC: 255914 AN: 1026344

Other (OTH) AF: 0.232 AC: 12441 AN: 53546

GnomAD4 genome AF: 0.192 AC: 29260 AN: 152156 Hom.: 3471 Cov.: 31 AF XY: 0.193 AC XY: 14360 AN XY: 74402

African (AFR) AF: 0.0537 AC: 2229 AN: 41536

American (AMR) AF: 0.310 AC: 4747 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3472

East Asian (EAS) AF: 0.345 AC: 1771 AN: 5130

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4828

European-Finnish (FIN) AF: 0.160 AC: 1700 AN: 10620

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.240 AC: 16305 AN: 67952

Other (OTH) AF: 0.222 AC: 468 AN: 2112

Alfa AF: 0.215 Hom.: 734

Bravo AF: 0.196

Asia WGS AF: 0.286 AC: 993 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: 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	-0.75
CADD	Benign	7.7
DANN	Benign	0.81
PhyloP100		0.16
PromoterAI		-0.061	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3752041; hg19: chr17-78010548; COSMIC: COSV53899748; COSMIC: COSV53899748;