17-44901029-G-C

Position:

chr17-44901029-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CCDC103	NM_213607.3 linkuse as main transcript	c.31G>C	p.Ala11Pro	missense_variant	2/4	ENST00000417826.3	NP_998772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC103	ENST00000417826.3 linkuse as main transcript	c.31G>C	p.Ala11Pro	missense_variant	2/4	1	NM_213607.3	ENSP00000391692	P1	Q8IW40-1

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

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:

AN:

239728

Hom.:

AF XY:

0.000246

AC XY:

AN XY:

130170

show subpopulations

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.:

Cov.:

AF XY:

0.000417

AC XY:

301

AN XY:

721944

show subpopulations

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:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74384

show subpopulations

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.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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:1Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;T;.;.;T;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.075

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.83

T;.;T;D;.;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Uncertain

0.064

MutationAssessor

Uncertain

2.8

.;M;.;M;M;.

MutationTaster

Benign

0.77

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

.;N;N;N;N;.

REVEL

Uncertain

0.42

Sift

Benign

0.066

.;T;T;T;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

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

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