3-180616670-C-T

Variant names:

• chr3-180616670-C-T
• rs61733583
• NM_181426.2:c.2432G>A

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.2432G>A​(p.Arg811His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,590,776 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R811C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (68 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.28
• Publications: 11 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 (MetaRNN=0.005194932).
• BP6: Variant 3-180616670-C-T is Benign according to our data. Variant chr3-180616670-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00515 (783/152128) while in subpopulation EAS AF = 0.0512 (265/5174). AF 95% confidence interval is 0.0462. There are 9 homozygotes in GnomAd4. There are 404 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.2432G>A	p.Arg811His	missense	Exon 18 of 20	NP_852091.1
	TTC14	NM_001288582.2		c.1775-710C>T		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.2432G>A	p.Arg811His	missense	Exon 18 of 20	ENSP00000417960.2
	TTC14	ENST00000382584.8	TSL:1	c.1775-710C>T		intron	N/A	ENSP00000372027.4
	CCDC39	ENST00000651046.1		c.2240G>A	p.Arg747His	missense	Exon 17 of 19	ENSP00000499175.1

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 783 AN: 152010 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00768

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0511

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00376

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00812 AC: 1741 AN: 214414 AF XY: 0.00803

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00560

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.0562

Gnomad FIN exome AF: 0.000603

Gnomad NFE exome AF: 0.00379

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00497 AC: 7153 AN: 1438648 Hom.: 68 Cov.: 31 AF XY: 0.00508 AC XY: 3626 AN XY: 713644

African (AFR) AF: 0.00160 AC: 53 AN: 33110

American (AMR) AF: 0.00572 AC: 236 AN: 41288

Ashkenazi Jewish (ASJ) AF: 0.00687 AC: 176 AN: 25618

East Asian (EAS) AF: 0.0440 AC: 1721 AN: 39104

South Asian (SAS) AF: 0.00677 AC: 566 AN: 83648

European-Finnish (FIN) AF: 0.000386 AC: 20 AN: 51838

Middle Eastern (MID) AF: 0.0180 AC: 103 AN: 5728

European-Non Finnish (NFE) AF: 0.00349 AC: 3834 AN: 1098856

Other (OTH) AF: 0.00747 AC: 444 AN: 59458

GnomAD4 genome AF: 0.00515 AC: 783 AN: 152128 Hom.: 9 Cov.: 32 AF XY: 0.00543 AC XY: 404 AN XY: 74362

African (AFR) AF: 0.00176 AC: 73 AN: 41510

American (AMR) AF: 0.00767 AC: 117 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5174

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4822

European-Finnish (FIN) AF: 0.000567 AC: 6 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00377 AC: 256 AN: 67988

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00515 Hom.: 29

Bravo AF: 0.00602

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00164 AC: 6

ESP6500EA AF: 0.00405 AC: 33

ExAC AF: 0.00709 AC: 852

Asia WGS AF: 0.0200 AC: 69 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg811His in exon 18 of CCDC39: This variant is not expected to have clinical si gnificance because it has been identified in 6.2% (12/194) of Han Chinese chromo somes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.n ih.gov/projects/SNP; dbSNP rs61733583).

Primary ciliary dyskinesia Benign:2

Feb 19, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 14 Benign:2

Jan 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.3
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.064	T
Polyphen		0.99	D
Vest4		0.43
MVP		0.80
MPC		0.32
ClinPred		0.023	T
GERP RS		5.1
PromoterAI		-0.0080	Neutral
Varity_R		0.15
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61733583; hg19: chr3-180334458; COSMIC: COSV56486993; COSMIC: COSV56486993;