rs74349463

Positions:

• chr17-44901658-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The NM_001258399.2(CCDC103):​c.280+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,454 control chromosomes in the GnomAD database, including 19,755 homozygotes. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1376 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18379 hom.)
• Consequence: CCDC103 NM_001258399.2 splice_donor, intron
• Scores: Splicing: ADA: 0.08650
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.298

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 Benign. Variant got -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.9, offset of -4, new splice context is: ccgGTaggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 17-44901658-T-C is Benign according to our data. Variant chr17-44901658-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 263318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC103	NM_213607.3	c.276+6T>C		splice_region_variant, intron_variant		ENST00000417826.3	NP_998772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC103	ENST00000417826.3	c.276+6T>C		splice_region_variant, intron_variant		1	NM_213607.3	ENSP00000391692.2
CCDC103	ENST00000410006.6	c.276+6T>C		splice_region_variant, intron_variant		2		ENSP00000387252.1
CCDC103	ENST00000357776.6	c.276+6T>C		splice_region_variant, intron_variant		2		ENSP00000350420.2
CCDC103	ENST00000410027.5	c.276+6T>C		splice_region_variant, intron_variant		4		ENSP00000386640.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19130 AN: 152086 Hom.: 1378 Cov.: 32

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.00867

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.134 AC: 33561 AN: 250970 Hom.: 2708 AF XY: 0.140 AC XY: 18960 AN XY: 135622

Gnomad AFR exome AF: 0.0605

Gnomad AMR exome AF: 0.0722

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.00734

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.155 AC: 226189 AN: 1461250 Hom.: 18379 Cov.: 32 AF XY: 0.156 AC XY: 113169 AN XY: 726926

Gnomad4 AFR exome AF: 0.0623

Gnomad4 AMR exome AF: 0.0755

Gnomad4 ASJ exome AF: 0.181

Gnomad4 EAS exome AF: 0.00529

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.165

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.126 AC: 19125 AN: 152204 Hom.: 1376 Cov.: 32 AF XY: 0.123 AC XY: 9187 AN XY: 74398

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.0930

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.00869

Gnomad4 SAS AF: 0.159

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.128

Alfa AF: 0.153 Hom.: 859

Bravo AF: 0.117

Asia WGS AF: 0.0830 AC: 288 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Primary ciliary dyskinesia 17 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
BayesDel_noAF	Benign	-0.79
CADD	Benign	12
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.086
dbscSNV1_RF	Benign	0.18
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: rs74349463; hg19: chr17-42979026;