Genetic Variant GCC2:p.Lys129Glu (chr2-108469714-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181453.4(GCC2):c.385A>G(p.Lys129Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GCC2
NM_181453.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

Publications

2 publications found

Variant links:

Genes affected

GCC2 (HGNC:23218): (GRIP and coiled-coil domain containing 2) The protein encoded by this gene is a peripheral membrane protein localized to the trans-Golgi network. It is sensitive to brefeldin A. This encoded protein contains a GRIP domain which is thought to be used in targeting. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2009]

GCC2 links:

GCC2-AS1 (HGNC:28126): (GCC2 antisense RNA 1)

GCC2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.089683294).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181453.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCC2	NM_181453.4	MANE Select	c.385A>G	p.Lys129Glu	missense	Exon 6 of 23	NP_852118.2	Q8IWJ2-1
	GCC2	NM_001410194.1		c.82A>G	p.Lys28Glu	missense	Exon 5 of 22	NP_001397123.1	A0A8I5QJB7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCC2	ENST00000309863.11	TSL:5 MANE Select	c.385A>G	p.Lys129Glu	missense	Exon 6 of 23	ENSP00000307939.5	Q8IWJ2-1
GCC2	ENST00000482325.5	TSL:1	n.*162A>G		non_coding_transcript_exon	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3
GCC2	ENST00000482325.5	TSL:1	n.*162A>G		3_prime_UTR	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152242

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000200

AC:

AN:

250504

AF XY:

0.0000222

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460204

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1110890

Other (OTH)

AF:

0.00

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5208

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.034

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.63

M_CAP

Benign

0.0051

MetaRNN

Benign

0.090

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

PhyloP100

1.9

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.91

REVEL

Benign

0.073

Sift

Benign

0.26

Sift4G

Benign

0.99

Polyphen

0.024

Vest4

0.16

MutPred

0.14

Loss of ubiquitination at K129 (P = 0.0134)

MVP

0.19

MPC

0.41

ClinPred

0.33

GERP RS

5.4

Varity_R

0.12

gMVP

0.15

Mutation Taster

=90/10

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over