Genetic Variant CCDC3:p.Lys223Met (chr10-12898561-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_031455.4(CCDC3):c.668A>T(p.Lys223Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,020 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

CCDC3
NM_031455.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.77

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34449717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC3	NM_031455.4 link	c.668A>T	p.Lys223Met	missense_variant	Exon 3 of 3	ENST00000378825.5	NP_113643.1	Q9BQI4-1
CCDC3	NM_001282658.2 link	c.293A>T	p.Lys98Met	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.668A>T	p.Lys223Met	missense_variant	Exon 3 of 3	1	NM_031455.4	ENSP00000368102.3	Q9BQI4-1
CCDC3	ENST00000378839.1 link	c.293A>T	p.Lys98Met	missense_variant	Exon 7 of 7	2		ENSP00000368116.1	Q9BQI4-2
ENSG00000285520	ENST00000649832.1 link	n.560T>A		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152214

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251458

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000540

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000701

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668A>T (p.K223M) alteration is located in exon 3 (coding exon 3) of the CCDC3 gene. This alteration results from a A to T substitution at nucleotide position 668, causing the lysine (K) at amino acid position 223 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.51

MutPred

0.33

Loss of methylation at K223 (P = 0.053);.;

MVP

0.25

MPC

0.52

ClinPred

0.93

GERP RS

4.3

Varity_R

0.45

gMVP

0.46

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