17-44901029-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_213607.3(CCDC103):c.31G>C(p.Ala11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,603,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: CCDC103 NM_213607.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.57

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20496407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC103	NM_213607.3	c.31G>C	p.Ala11Pro	missense_variant	2/4	ENST00000417826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC103	ENST00000417826.3	c.31G>C	p.Ala11Pro	missense_variant	2/4	1	NM_213607.3	P1

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000242 AC: 58 AN: 239728 Hom.: 0 AF XY: 0.000246 AC XY: 32 AN XY: 130170

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000437 AC: 634 AN: 1450840 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 301 AN XY: 721944

Gnomad4 AFR exome AF: 0.0000612

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000555

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74384

Gnomad4 AFR AF: 0.0000965

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: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000264 AC: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 17 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 03, 2019	The CCDC103 c.31G>C variant is classified as VUS (BS3) The CCDC103 c.31G>C variant is a single nucleotide change in exon 2 of 4 of the CCDC103 gene, which is predicted to change the amino acid alanine at position 11 in the protein to proline. Well established functional studies do not support a deleterious effect of this variant PMID:22581229. Performed functional studies in zebrafish. The p.Ala11Pro variant completely rescued the mutant phenotype indicating that the heterozygous p.Ala11Pro variant in the 1 PCD individual is a rare nonpathogenic polymorphism. (BS3). The variant has been reported in dbSNP (rs146015856) and in the HGMD database: Not present. It has not been reported in ClinVar. -

Primary ciliary dyskinesia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 21, 2022	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 11 of the CCDC103 protein (p.Ala11Pro). This variant is present in population databases (rs146015856, gnomAD 0.04%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 22581229). ClinVar contains an entry for this variant (Variation ID: 955334). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Benign	0.13
Eigen_PC	Benign	0.075
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.83	T;.;T;D;.;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Uncertain	0.064	D
MutationTaster	Benign	0.77	D;D;D
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.080	T;T;T;T;T;T
Polyphen		0.99	.;D;.;.;D;.
Vest4		0.56, 0.60, 0.56
MVP		0.80
MPC		0.73
ClinPred		0.097	T
GERP RS		3.7
Varity_R		0.33
gMVP		0.71

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: rs146015856; hg19: chr17-42978397;