Genetic Variant CCDC3:p.Arg236Pro (chr10-12898522-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_031455.4(CCDC3):c.707G>C(p.Arg236Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CCDC3
NM_031455.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.48

Variant links:

Genes affected

CCDC3 (HGNC:23813): (coiled-coil domain containing 3) Involved in negative regulation of gene expression; negative regulation of lipid metabolic process; and negative regulation of tumor necrosis factor-mediated signaling pathway. Located in endoplasmic reticulum and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

CCDC3 links:

ENSG00000285520 (HGNC:):

ENSG00000285520 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.353871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC3	NM_031455.4 link	c.707G>C	p.Arg236Pro	missense_variant	Exon 3 of 3	ENST00000378825.5	NP_113643.1	Q9BQI4-1
CCDC3	NM_001282658.2 link	c.332G>C	p.Arg111Pro	missense_variant	Exon 7 of 7		NP_001269587.1	Q9BQI4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC3	ENST00000378825.5 link	c.707G>C	p.Arg236Pro	missense_variant	Exon 3 of 3	1	NM_031455.4	ENSP00000368102.3	Q9BQI4-1
CCDC3	ENST00000378839.1 link	c.332G>C	p.Arg111Pro	missense_variant	Exon 7 of 7	2		ENSP00000368116.1	Q9BQI4-2
ENSG00000285520	ENST00000649832.1 link	n.521C>G		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

3.5

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.7

D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;.

Vest4

0.80

MutPred

0.22

Loss of MoRF binding (P = 0.0276);.;

MVP

0.092

MPC

0.58

ClinPred

1.0

GERP RS

5.4

Varity_R

0.87

gMVP

0.57

Mutation Taster

=41/59

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

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