rs142342712

chr17-44901651-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_213607.3(CCDC103):c.275C>T(p.Pro92Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P92P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CCDC103 NM_213607.3 missense, splice_region
• Scores: Splicing: ADA: 0.001156
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.173

Genes affected

CCDC103 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.012783974).
• BP6: Variant 17-44901651-C-T is Benign according to our data. Variant chr17-44901651-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411698.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC103	NM_213607.3	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	ENST00000417826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC103	ENST00000417826.3	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	1	NM_213607.3	P1
CCDC103	ENST00000410006.6	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	2		P1
CCDC103	ENST00000357776.6	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	2
CCDC103	ENST00000410027.5	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	4

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 251198 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135742

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.0000908 AC XY: 66 AN XY: 727188

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74460

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.000555

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 17, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 92 of the CCDC103 protein (p.Pro92Leu). This variant is present in population databases (rs142342712, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CCDC103-related conditions. ClinVar contains an entry for this variant (Variation ID: 411698). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 12, 2021	This alteration is classified as likely 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. -

Primary ciliary dyskinesia 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 13, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	15
Dann	Benign	0.79
DEOGEN2	Benign	0.061	T;.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.35	N
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;.;N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N;N;N;N;.
REVEL	Benign	0.21
Sift	Benign	0.30	T;T;D;T;.
Sift4G	Benign	0.26	T;T;D;T;T
Polyphen		0.0020	B;.;.;B;.
Vest4		0.10
MVP		0.30
MPC		0.19
ClinPred		0.0094	T
GERP RS		-3.8
Varity_R		0.039
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.12		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: rs142342712; hg19: chr17-42979019;