rs200913298

Variant names:

• chr3-180616933-A-G
• rs200913298
• NM_181426.2:c.2299T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_181426.2(CCDC39):​c.2299T>C​(p.Leu767Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,477,180 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L767L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: CCDC39 NM_181426.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.650
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-180616933-A-G is Benign according to our data. Variant chr3-180616933-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219954.
• BP7: Synonymous conserved (PhyloP=0.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00225 (342/152302) while in subpopulation NFE AF = 0.00415 (282/68020). AF 95% confidence interval is 0.00375. There are 1 homozygotes in GnomAd4. There are 164 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	NM_181426.2	MANE Select	c.2299T>C	p.Leu767Leu	synonymous	Exon 17 of 20	NP_852091.1
	TTC14	NM_001288582.2		c.1775-447A>G		intron	N/A	NP_001275511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.2299T>C	p.Leu767Leu	synonymous	Exon 17 of 20	ENSP00000417960.2
	TTC14	ENST00000382584.8	TSL:1	c.1775-447A>G		intron	N/A	ENSP00000372027.4
	CCDC39	ENST00000936067.1		c.2206T>C	p.Leu736Leu	synonymous	Exon 16 of 19	ENSP00000606126.1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00225 AC: 473 AN: 210540 AF XY: 0.00207

Gnomad AFR exome AF: 0.000221

Gnomad AMR exome AF: 0.000277

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00341

Gnomad NFE exome AF: 0.00414

Gnomad OTH exome AF: 0.00211

GnomAD4 exome AF: 0.00350 AC: 4642 AN: 1324878 Hom.: 15 Cov.: 24 AF XY: 0.00349 AC XY: 2315 AN XY: 662576

African (AFR) AF: 0.000371 AC: 11 AN: 29684

American (AMR) AF: 0.000226 AC: 9 AN: 39808

Ashkenazi Jewish (ASJ) AF: 0.0000402 AC: 1 AN: 24858

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38682

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78370

European-Finnish (FIN) AF: 0.00387 AC: 197 AN: 50924

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00432 AC: 4331 AN: 1001480

Other (OTH) AF: 0.00164 AC: 91 AN: 55582

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74468

African (AFR) AF: 0.000433 AC: 18 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00415 AC: 282 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00299 Hom.: 1

Bravo AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.99
DANN	Benign	0.66
PhyloP100		0.65
PromoterAI		-0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
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: rs200913298; hg19: chr3-180334721;