chr17-44901651-C-T

Position:

chr17-44901651-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

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).

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:2B:1

Conservation

PhyloP100: 0.173

Variant links:

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]

CCDC103 links:

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ACMG classification

Classification made for transcript

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: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC103	NM_213607.3 linkuse as main transcript	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	ENST00000417826.3	NP_998772.1	Q8IW40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CCDC103	ENST00000417826.3 linkuse as main transcript	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	1	NM_213607.3	ENSP00000391692.2	Q8IW40-1
CCDC103	ENST00000410006.6 linkuse as main transcript	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	2		ENSP00000387252.1	Q8IW40-1
CCDC103	ENST00000357776.6 linkuse as main transcript	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	2		ENSP00000350420.2	F8W6J8
CCDC103	ENST00000410027.5 linkuse as main transcript	c.275C>T	p.Pro92Leu	missense_variant, splice_region_variant	3/4	4		ENSP00000386640.1	Q8IW40-2

Frequencies

GnomAD3 genomes

AF:

0.000499

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

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:

AN:

251198

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135742

show subpopulations

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.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727188

show subpopulations

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:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74460

show subpopulations

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.:

Bravo

AF:

0.000555

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

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

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.061

T;.;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.45

.;T;T;.;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

N;.;N;N;.

PrimateAI

Benign

0.22

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over