Genetic Variant NM_018017.4:c.536G>A (chr10-114162733-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018017.4(CCDC186):c.536G>A(p.Arg179Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0733 in 1,613,686 control chromosomes in the GnomAD database, including 4,984 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.057 ( 339 hom., cov: 33)

Exomes 𝑓: 0.075 ( 4645 hom. )

Consequence

CCDC186
NM_018017.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.428

Publications

17 publications found

Variant links:

Genes affected

CCDC186 (HGNC:24349): (coiled-coil domain containing 186) Predicted to enable small GTPase binding activity. Predicted to be involved in vesicle cytoskeletal trafficking. Predicted to act upstream of or within insulin secretion involved in cellular response to glucose stimulus and response to bacterium. Predicted to be located in Golgi apparatus. Predicted to be active in trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

CCDC186 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013920665).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC186	NM_018017.4 link	c.536G>A	p.Arg179Gln	missense_variant	Exon 2 of 16	ENST00000369287.8	NP_060487.2	Q7Z3E2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC186	ENST00000369287.8 link	c.536G>A	p.Arg179Gln	missense_variant	Exon 2 of 16	1	NM_018017.4	ENSP00000358293.3	Q7Z3E2
CCDC186	ENST00000369286.1 link	c.536G>A	p.Arg179Gln	missense_variant	Exon 2 of 2	1		ENSP00000358292.1	A0A0C4DFU7
CCDC186	ENST00000648613.1 link	c.536G>A	p.Arg179Gln	missense_variant	Exon 3 of 17			ENSP00000498136.1	Q7Z3E2
CCDC186	ENST00000369285.7 link	c.536G>A	p.Arg179Gln	missense_variant	Exon 3 of 3	2		ENSP00000358291.3	A0A0C4DFU7

Frequencies

GnomAD3 genomes

AF:

0.0571

AC:

8689

AN:

152074

Hom.:

339

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.0769

Gnomad AMR

AF:

0.0713

Gnomad ASJ

AF:

0.0741

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.0817

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0815

Gnomad OTH

AF:

0.0672

GnomAD2 exomes

AF:

0.0555

AC:

13923

AN:

251008

AF XY:

0.0552

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.0459

Gnomad ASJ exome

AF:

0.0708

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0715

Gnomad NFE exome

AF:

0.0801

Gnomad OTH exome

AF:

0.0721

GnomAD4 exome

AF:

0.0750

AC:

109643

AN:

1461494

Hom.:

4645

Cov.:

AF XY:

0.0731

AC XY:

53166

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.0149

AC:

499

AN:

33470

American (AMR)

AF:

0.0476

AC:

2127

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0730

AC:

1906

AN:

26118

East Asian (EAS)

AF:

0.000277

AC:

AN:

39668

South Asian (SAS)

AF:

0.00848

AC:

731

AN:

86222

European-Finnish (FIN)

AF:

0.0746

AC:

3981

AN:

53390

Middle Eastern (MID)

AF:

0.0432

AC:

249

AN:

5764

European-Non Finnish (NFE)

AF:

0.0864

AC:

96032

AN:

1111796

Other (OTH)

AF:

0.0680

AC:

4107

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

5355

10710

16066

21421

26776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3498

6996

10494

13992

17490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0571

AC:

8689

AN:

152192

Hom.:

339

Cov.:

AF XY:

0.0559

AC XY:

4158

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0160

AC:

666

AN:

41540

American (AMR)

AF:

0.0712

AC:

1088

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0741

AC:

257

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00766

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0817

AC:

864

AN:

10572

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0815

AC:

5542

AN:

67996

Other (OTH)

AF:

0.0665

AC:

140

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

430

860

1289

1719

2149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0740

Hom.:

1729

Bravo

AF:

0.0562

TwinsUK

AF:

0.0903

AC:

335

ALSPAC

AF:

0.0929

AC:

358

ESP6500AA

AF:

0.0209

AC:

ESP6500EA

AF:

0.0826

AC:

710

ExAC

AF:

0.0535

AC:

6493

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0904

EpiControl

AF:

0.0855

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.76

CADD

Benign

9.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;T;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.64

.;T;.;T

MetaRNN

Benign

0.0014

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.43

PROVEAN

Benign

-0.060

N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.67

T;.;T;T

Sift4G

Benign

0.58

T;.;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.073

MPC

0.31

ClinPred

0.011

GERP RS

-1.3

Varity_R

0.018

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(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

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over