Genetic Variant CCDC103:p.Thr21Ala (chr17-44901059-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_213607.3(CCDC103):c.61A>G(p.Thr21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,601,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CCDC103
NM_213607.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.69

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 -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01475516).

BP6

Variant 17-44901059-A-G is Benign according to our data. Variant chr17-44901059-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3138230.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC103	NM_213607.3 link	c.61A>G	p.Thr21Ala	missense_variant	Exon 2 of 4	ENST00000417826.3	NP_998772.1	Q8IW40-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC103	ENST00000417826.3 link	c.61A>G	p.Thr21Ala	missense_variant	Exon 2 of 4	1	NM_213607.3	ENSP00000391692.2		Q8IW40-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000253

AC:

AN:

237624

Hom.:

AF XY:

0.00000775

AC XY:

AN XY:

129108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000348

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000552

AC:

AN:

1448782

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000262

AC:

AN:

152396

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000770

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:1

May 27, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Benign

0.060

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.3

DANN

Benign

0.82

DEOGEN2

Benign

0.018

.;T;.;.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.52

T;.;T;T;.;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.015

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.3

.;N;.;N;N;.

PrimateAI

Benign

0.30

PROVEAN

Benign

1.1

.;N;N;N;N;.

REVEL

Benign

0.22

Sift

Benign

0.66

.;T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

.;B;.;.;B;.

Vest4

0.059, 0.049, 0.057

MutPred

0.27

Loss of phosphorylation at T21 (P = 0.0546);Loss of phosphorylation at T21 (P = 0.0546);Loss of phosphorylation at T21 (P = 0.0546);Loss of phosphorylation at T21 (P = 0.0546);Loss of phosphorylation at T21 (P = 0.0546);Loss of phosphorylation at T21 (P = 0.0546);

MVP

0.28

MPC

0.19

ClinPred

0.019

GERP RS

-2.5

Varity_R

0.034

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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