Variant 10-114126038-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018017.4(CCDC186):c.2461A>C(p.Lys821Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CCDC186
NM_018017.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90

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:

CCDC186 (HGNC:):

CCDC186 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC186	NM_018017.4 linkuse as main transcript	c.2461A>C	p.Lys821Gln	missense_variant	15/16	ENST00000369287.8	NP_060487.2	Q7Z3E2
CCDC186	NM_001321829.1 linkuse as main transcript	c.2461A>C	p.Lys821Gln	missense_variant	16/17		NP_001308758.1	Q7Z3E2Q496Y1
CCDC186	XM_011539915.4 linkuse as main transcript	c.1720A>C	p.Lys574Gln	missense_variant	14/15		XP_011538217.1
CCDC186	NR_135815.1 linkuse as main transcript	n.3340A>C		non_coding_transcript_exon_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CCDC186	ENST00000369287.8 linkuse as main transcript	c.2461A>C	p.Lys821Gln	missense_variant	15/16	1	NM_018017.4	ENSP00000358293.3	Q7Z3E2
CCDC186	ENST00000648613.1 linkuse as main transcript	c.2461A>C	p.Lys821Gln	missense_variant	16/17			ENSP00000498136.1	Q7Z3E2
CCDC186	ENST00000428953.1 linkuse as main transcript	c.1278-812A>C		intron_variant		2		ENSP00000415344.1	H0Y7V5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251110

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135696

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727150

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.2461A>C (p.K821Q) alteration is located in exon 15 (coding exon 14) of the CCDC186 gene. This alteration results from a A to C substitution at nucleotide position 2461, causing the lysine (K) at amino acid position 821 to be replaced by a glutamine (Q). 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

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Benign

-0.63

PROVEAN

Uncertain

-3.3

D;.

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.84

MutPred

0.31

Loss of methylation at K821 (P = 0.0075);Loss of methylation at K821 (P = 0.0075);

MVP

0.49

MPC

0.98

ClinPred

0.99

GERP RS

5.8

Varity_R

0.76

gMVP

0.58

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