rs201097154

Variant names:

• chr3-180616545-G-A
• rs201097154
• NM_181426.2:c.2557C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181426.2(CCDC39):​c.2557C>T​(p.Arg853Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,584,308 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: CCDC39 NM_181426.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.0120
• Publications: 6 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07119599).

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.2557C>T	p.Arg853Cys	missense	Exon 18 of 20	NP_852091.1	Q9UFE4-1
	TTC14	NM_001288582.2		c.1775-835G>A		intron	N/A	NP_001275511.1	Q96N46-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC39	ENST00000476379.6	TSL:2 MANE Select	c.2557C>T	p.Arg853Cys	missense	Exon 18 of 20	ENSP00000417960.2	Q9UFE4-1
	TTC14	ENST00000382584.8	TSL:1	c.1775-835G>A		intron	N/A	ENSP00000372027.4	Q96N46-2
	CCDC39	ENST00000936067.1		c.2464C>T	p.Arg822Cys	missense	Exon 17 of 19	ENSP00000606126.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000354 AC: 81 AN: 229114 AF XY: 0.000371

Gnomad AFR exome AF: 0.000275

Gnomad AMR exome AF: 0.0000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.000595

Gnomad OTH exome AF: 0.000180

GnomAD4 exome AF: 0.000231 AC: 331 AN: 1432294 Hom.: 1 Cov.: 30 AF XY: 0.000239 AC XY: 170 AN XY: 710348

African (AFR) AF: 0.000185 AC: 6 AN: 32456

American (AMR) AF: 0.0000489 AC: 2 AN: 40896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.000174 AC: 14 AN: 80538

European-Finnish (FIN) AF: 0.000344 AC: 18 AN: 52320

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5592

European-Non Finnish (NFE) AF: 0.000254 AC: 279 AN: 1097222

Other (OTH) AF: 0.000186 AC: 11 AN: 59176

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74260

African (AFR) AF: 0.000169 AC: 7 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15246

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000438 Hom.: 2

Bravo AF: 0.000268

ESP6500AA AF: 0.000274 AC: 1

ESP6500EA AF: 0.000615 AC: 5

ExAC AF: 0.000414 AC: 50

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.012
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.38
Sift	Benign	0.12	T
Sift4G	Benign	0.083	T
Polyphen		0.97	D
Vest4		0.39
MVP		0.60
MPC		0.29
ClinPred		0.068	T
GERP RS		-0.88
PromoterAI		-0.010	Neutral
Varity_R		0.051
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201097154; hg19: chr3-180334333; COSMIC: COSV56494852;