rs112738198

chr3-180659741-G-Cchr3-180659741-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_181426.2(CCDC39):c.545C>G(p.Thr182Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0318 in 1,610,888 control chromosomes in the GnomAD database, including 971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (73 hom., cov: 32)
  • Exomes 𝑓: 0.032 (898 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.82

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033574104).
• BP6: Variant 3-180659741-G-C is Benign according to our data. Variant chr3-180659741-G-C is described in ClinVar as [Benign]. Clinvar id is 162844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-180659741-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3828/152228) while in subpopulation NFE AF= 0.0391 (2660/67974). AF 95% confidence interval is 0.0379. There are 73 homozygotes in gnomad4. There are 1820 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 73 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC39	NM_181426.2	c.545C>G	p.Thr182Ser	missense_variant	5/20	ENST00000476379.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC39	ENST00000476379.6	c.545C>G	p.Thr182Ser	missense_variant	5/20	2	NM_181426.2	P2

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3828 AN: 152110 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.00668

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0391

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0241 AC: 5985 AN: 248098 Hom.: 97 AF XY: 0.0239 AC XY: 3214 AN XY: 134646

Gnomad AFR exome AF: 0.00530

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.00767

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00528

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0278

GnomAD4 exome AF: 0.0325 AC: 47386 AN: 1458660 Hom.: 898 Cov.: 31 AF XY: 0.0320 AC XY: 23217 AN XY: 725682

Gnomad4 AFR exome AF: 0.00568

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.00858

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00583

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.0251 AC: 3828 AN: 152228 Hom.: 73 Cov.: 32 AF XY: 0.0244 AC XY: 1820 AN XY: 74446

Gnomad4 AFR AF: 0.00666

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.0331

Gnomad4 NFE AF: 0.0391

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0310 Hom.: 70

Bravo AF: 0.0235

TwinsUK AF: 0.0388 AC: 144

ALSPAC AF: 0.0381 AC: 147

ESP6500AA AF: 0.00936 AC: 34

ESP6500EA AF: 0.0323 AC: 263

ExAC AF: 0.0245 AC: 2958

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0391

EpiControl AF: 0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr182Ser in exon 5 of CCDC39: This variant is not expected to have clinical sig nificance because it has been identified in 3.2% (263/8154) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs112738198). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 30, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Primary ciliary dyskinesia 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Uncertain	0.022	D
Sift4G	Benign	0.18	T
Polyphen		0.98	D
Vest4		0.15
MutPred		0.14		Gain of glycosylation at T182 (P = 0.096);
MPC		0.14
ClinPred		0.036	T
GERP RS		4.0
Varity_R		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs112738198; hg19: chr3-180377529;