chr17-44902645-C-CAG

Position:

• chr17-44902645-C-CAG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000417826.3(CCDC103):​c.568_569dup​(p.Ser190ArgfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A186A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CCDC103 ENST00000417826.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -3.23

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.236 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44902645-C-CAG is Pathogenic according to our data. Variant chr17-44902645-C-CAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 455029.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC103	NM_213607.3	c.568_569dup	p.Ser190ArgfsTer19	frameshift_variant	4/4	ENST00000417826.3	NP_998772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC103	ENST00000417826.3	c.568_569dup	p.Ser190ArgfsTer19	frameshift_variant	4/4	1	NM_213607.3	ENSP00000391692	P1
CCDC103	ENST00000357776.6	c.568_569dup	p.Ser190ArgfsTer19	frameshift_variant	4/4	2		ENSP00000350420
CCDC103	ENST00000410006.6	c.568_569dup	p.Ser190ArgfsTer19	frameshift_variant	4/4	2		ENSP00000387252	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change creates a premature translational stop signal (p.Ser190Argfs*19) in the CCDC103 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the CCDC103 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 455029). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Primary ciliary dyskinesia;C4022986:Absent inner and outer dynein arms;C4551493:Situs inversus Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS)

Nov 04, 2018

This CCDC103 novel homozygous frameshift variant was found in a patient with situs-inversus-totalis and primary ciliary dyskinesia, whose axoneme lack dynein arms and nexin links in the axonemes. The gene and protein expression are reduced. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs746242380; hg19: chr17-42980013;