rs10693712

Variant names:

• chr17-80090346-A-ACAC
• rs10693712
• NM_017950.4:c.2832+462_2832+463insCAC

Your query was ambiguous. Multiple possible variants found:

• chr17-80090346-A-ACAC
• chr17-80090346-A-AC
• chr17-80090346-A-ACACGGGACGCGCGCAGGCAAGTGCACGAACAACAC
• chr17-80090346-A-ACACGGGACGCGCGCAGGCACGTGCACGAACAACAC
• chr17-80090346-A-ACAT
• chr17-80090346-A-ACCC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_001243342.2(CCDC40):​c.3040_3041insCAC​(p.Thr1013dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0322 in 426,652 control chromosomes in the GnomAD database, including 945 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1014R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (68 hom., cov: 0)
  • Exomes 𝑓: 0.032 (877 hom.)
• Consequence: CCDC40 NM_001243342.2 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0180
• Publications: 7 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 -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001243342.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 17-80090346-A-ACAC is Benign according to our data. Variant chr17-80090346-A-ACAC is described in ClinVar as Benign. ClinVar VariationId is 218550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243342.2. 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.2832+462_2832+463insCAC		intron	N/A	NP_060420.2
	CCDC40	NM_001243342.2		c.3040_3041insCAC	p.Thr1013dup	disruptive_inframe_insertion	Exon 18 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.2832+462_2832+463insCAC		intron	N/A	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.2369+462_2369+463insCAC		intron	N/A
	CCDC40	ENST00000374877.7	TSL:5	c.3040_3041insCAC	p.Thr1013dup	disruptive_inframe_insertion	Exon 18 of 18	ENSP00000364011.3	Q4G0X9-2

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 567 AN: 19316 Hom.: 68 Cov.: 0

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.0301

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0219

Gnomad SAS AF: 0.0649

Gnomad FIN AF: 0.0576

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.295 AC: 19150 AN: 65002 AF XY: 0.320

Gnomad AFR exome AF: 0.0947

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.0957

Gnomad FIN exome AF: 0.495

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.0324 AC: 13186 AN: 407314 Hom.: 877 Cov.: 43 AF XY: 0.0333 AC XY: 6912 AN XY: 207388

African (AFR) AF: 0.0583 AC: 713 AN: 12228

American (AMR) AF: 0.0170 AC: 289 AN: 16960

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 367 AN: 7562

East Asian (EAS) AF: 0.0100 AC: 158 AN: 15764

South Asian (SAS) AF: 0.0387 AC: 1116 AN: 28800

European-Finnish (FIN) AF: 0.0447 AC: 688 AN: 15394

Middle Eastern (MID) AF: 0.126 AC: 226 AN: 1794

European-Non Finnish (NFE) AF: 0.0309 AC: 8951 AN: 289752

Other (OTH) AF: 0.0356 AC: 678 AN: 19060

GnomAD4 genome AF: 0.0294 AC: 568 AN: 19338 Hom.: 68 Cov.: 0 AF XY: 0.0305 AC XY: 291 AN XY: 9548

African (AFR) AF: 0.0253 AC: 158 AN: 6256

American (AMR) AF: 0.0154 AC: 49 AN: 3192

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 5 AN: 270

East Asian (EAS) AF: 0.0219 AC: 19 AN: 868

South Asian (SAS) AF: 0.0659 AC: 24 AN: 364

European-Finnish (FIN) AF: 0.0576 AC: 44 AN: 764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 14

European-Non Finnish (NFE) AF: 0.0361 AC: 260 AN: 7200

Other (OTH) AF: 0.0164 AC: 4 AN: 244

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.018
Mutation Taster		=83/17	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10693712; hg19: chr17-78064145; COSMIC: COSV66472588; COSMIC: COSV66472588;