3-180616954-T-C

Position:

• chr3-180616954-T-C

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.2278A>G​(p.Thr760Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,412,530 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (26 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025066435).
• BP6: Variant 3-180616954-T-C is Benign according to our data. Variant chr3-180616954-T-C is described in ClinVar as [Benign]. Clinvar id is 226484.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 = 0.00943 (1437/152344) while in subpopulation AFR AF= 0.0332 (1379/41578). AF 95% confidence interval is 0.0317. There are 27 homozygotes in gnomad4. There are 667 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC39	NM_181426.2	c.2278A>G	p.Thr760Ala	missense_variant	17/20	ENST00000476379.6	NP_852091.1
TTC14	NM_001288582.2	c.1775-426T>C		intron_variant			NP_001275511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC39	ENST00000476379.6	c.2278A>G	p.Thr760Ala	missense_variant	17/20	2	NM_181426.2	ENSP00000417960	P2

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1436 AN: 152226 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00270 AC: 456 AN: 168884 Hom.: 6 AF XY: 0.00222 AC XY: 203 AN XY: 91270

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000776

Gnomad SAS exome AF: 0.000243

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000836 AC: 1054 AN: 1260186 Hom.: 26 Cov.: 21 AF XY: 0.000771 AC XY: 484 AN XY: 627734

Gnomad4 AFR exome AF: 0.0319

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.000112

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000115

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00943 AC: 1437 AN: 152344 Hom.: 27 Cov.: 32 AF XY: 0.00895 AC XY: 667 AN XY: 74500

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00294 Hom.: 5

Bravo AF: 0.0111

ESP6500AA AF: 0.0344 AC: 123

ESP6500EA AF: 0.000124 AC: 1

ExAC AF: 0.00304 AC: 362

Asia WGS AF: 0.00231 AC: 8 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Thr760Ala in exon 17 of CCDC39: This variant is not expected to have clinical si gnificance because it has been identified in 3.4% (123/3574) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs79386936). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2022

- -

Primary ciliary dyskinesia 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	0.15
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0036	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;N;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.26
Sift	Benign	0.21	T
Sift4G	Benign	0.26	T
Polyphen		0.82	P
Vest4		0.35
MVP		0.68
MPC		0.090
ClinPred		0.0067	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.085

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

Publications

LitVar

Other links and lift over

dbSNP: rs79386936; hg19: chr3-180334742; COSMIC: COSV99059802; COSMIC: COSV99059802;