NM_181426.2:c.1363-13delT

Variant names:

• chr3-180647255-TA-T
• rs374074877
• NM_181426.2:c.1363-13delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_181426.2(CCDC39):​c.1363-13delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,152,244 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 29)
  • Exomes 𝑓: 0.031 (4 hom.)
• Consequence: CCDC39 NM_181426.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.273
• Publications: 0 publications found

Genes affected

CCDC39 (HGNC:25244): (coiled-coil domain 39 molecular ruler complex subunit) The protein encoded by this gene is involved in the motility of cilia and flagella. The encoded protein is essential for the assembly of dynein regulatory and inner dynein arm complexes, which regulate ciliary beat. Defects in this gene are a cause of primary ciliary dyskinesia type 14 (CILD14). [provided by RefSeq, Jul 2011]

CCDC39 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-180647255-TA-T is Benign according to our data. Variant chr3-180647255-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 344268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0037 (534/144406) while in subpopulation AFR AF = 0.0112 (440/39314). AF 95% confidence interval is 0.0103. There are 1 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181426.2. 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
	CCDC39	NM_181426.2	MANE Select	c.1363-13delT		intron	N/A	NP_852091.1	Q9UFE4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.1363-13delT		intron	N/A	ENSP00000417960.2	Q9UFE4-1
	CCDC39	ENST00000936067.1		c.1270-13delT		intron	N/A	ENSP00000606126.1
	CCDC39	ENST00000651046.1		c.1171-13delT		intron	N/A	ENSP00000499175.1	A0A494C1Q3

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 534 AN: 144342 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000792

Gnomad OTH AF: 0.00204

GnomAD2 exomes AF: 0.0746 AC: 5637 AN: 75564 AF XY: 0.0773

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.0987

Gnomad ASJ exome AF: 0.0837

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.0430

Gnomad NFE exome AF: 0.0624

Gnomad OTH exome AF: 0.0829

GnomAD4 exome AF: 0.0313 AC: 31548 AN: 1007838 Hom.: 4 Cov.: 24 AF XY: 0.0323 AC XY: 15971 AN XY: 493986

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0554 AC: 1142 AN: 20618

American (AMR) AF: 0.0538 AC: 986 AN: 18320

Ashkenazi Jewish (ASJ) AF: 0.0465 AC: 727 AN: 15622

East Asian (EAS) AF: 0.0671 AC: 1478 AN: 22026

South Asian (SAS) AF: 0.0492 AC: 2409 AN: 48982

European-Finnish (FIN) AF: 0.0307 AC: 1099 AN: 35782

Middle Eastern (MID) AF: 0.0235 AC: 98 AN: 4166

European-Non Finnish (NFE) AF: 0.0276 AC: 22134 AN: 801724

Other (OTH) AF: 0.0363 AC: 1475 AN: 40598

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00370 AC: 534 AN: 144406 Hom.: 1 Cov.: 29 AF XY: 0.00321 AC XY: 225 AN XY: 70034

African (AFR) AF: 0.0112 AC: 440 AN: 39314

American (AMR) AF: 0.00111 AC: 16 AN: 14460

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3358

East Asian (EAS) AF: 0.000200 AC: 1 AN: 4996

South Asian (SAS) AF: 0.000218 AC: 1 AN: 4588

European-Finnish (FIN) AF: 0.00213 AC: 19 AN: 8924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000792 AC: 52 AN: 65628

Other (OTH) AF: 0.00203 AC: 4 AN: 1972

Alfa AF: 0.0450 Hom.: 89

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	Primary ciliary dyskinesia 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374074877; hg19: chr3-180365043; COSMIC: COSV56481730;