chr3-180616275-G-A

Variant names:

• chr3-180616275-G-A
• rs57859179
• NM_181426.2:c.2669+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181426.2(CCDC39):​c.2669+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,612,398 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (11 hom.)
• Consequence: CCDC39 NM_181426.2 splice_region, intron
• Scores: Splicing: ADA: 0.00001458
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.616
• Publications: 1 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]

TTC14 (HGNC:24697): (tetratricopeptide repeat domain 14) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000145075 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-180616275-G-A is Benign according to our data. Variant chr3-180616275-G-A is described in ClinVar as Benign. ClinVar VariationId is 242174.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 = 0.00572 (870/152144) while in subpopulation AFR AF = 0.0195 (808/41502). AF 95% confidence interval is 0.0184. There are 7 homozygotes in GnomAd4. There are 383 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2669+6C>T		splice_region intron	N/A	NP_852091.1
	TTC14	NM_001288582.2		c.1775-1105G>A		intron	N/A	NP_001275511.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.2669+6C>T		splice_region intron	N/A	ENSP00000417960.2
	TTC14	ENST00000382584.8	TSL:1	c.1775-1105G>A		intron	N/A	ENSP00000372027.4
	CCDC39	ENST00000936067.1		c.2576+6C>T		splice_region intron	N/A	ENSP00000606126.1

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 868 AN: 152026 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00145 AC: 360 AN: 248574 AF XY: 0.00105

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.000932

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000749 AC: 1093 AN: 1460254 Hom.: 11 Cov.: 30 AF XY: 0.000648 AC XY: 471 AN XY: 726400

African (AFR) AF: 0.0211 AC: 704 AN: 33420

American (AMR) AF: 0.00101 AC: 45 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00348 AC: 20 AN: 5754

European-Non Finnish (NFE) AF: 0.000160 AC: 178 AN: 1110816

Other (OTH) AF: 0.00209 AC: 126 AN: 60320

GnomAD4 genome AF: 0.00572 AC: 870 AN: 152144 Hom.: 7 Cov.: 32 AF XY: 0.00515 AC XY: 383 AN XY: 74396

African (AFR) AF: 0.0195 AC: 808 AN: 41502

American (AMR) AF: 0.00210 AC: 32 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67998

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00290 Hom.: 4

Bravo AF: 0.00600

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia 14 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.3
DANN	Benign	0.71
PhyloP100		0.62
PromoterAI		0.0077	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs57859179; hg19: chr3-180334063;