Genetic Variant GCC2:p.His124Arg (chr2-108469700-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_181453.4(GCC2):c.371A>G(p.His124Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,612,216 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 21 hom. )

Consequence

GCC2
NM_181453.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.358

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022194684).

BP6

Variant 2-108469700-A-G is Benign according to our data. Variant chr2-108469700-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3042982.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.371A>G	p.His124Arg	missense	Exon 6 of 23	NP_852118.2	Q8IWJ2-1
	GCC2	NM_001410194.1		c.68A>G	p.His23Arg	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.371A>G	p.His124Arg	missense	Exon 6 of 23	ENSP00000307939.5	Q8IWJ2-1
GCC2	ENST00000482325.5	TSL:1	n.*148A>G		non_coding_transcript_exon	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3
GCC2	ENST00000482325.5	TSL:1	n.*148A>G		3_prime_UTR	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

432

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00405

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00257

AC:

642

AN:

249978

AF XY:

0.00234

show subpopulations

Gnomad AFR exome

AF:

0.000812

Gnomad AMR exome

AF:

0.000989

Gnomad ASJ exome

AF:

0.000897

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00366

Gnomad NFE exome

AF:

0.00439

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00397

AC:

5796

AN:

1459840

Hom.:

Cov.:

AF XY:

0.00386

AC XY:

2806

AN XY:

726260

show subpopulations

African (AFR)

AF:

0.000719

AC:

AN:

33394

American (AMR)

AF:

0.000853

AC:

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.000728

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

85930

European-Finnish (FIN)

AF:

0.00348

AC:

186

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00486

AC:

5397

AN:

1110758

Other (OTH)

AF:

0.00219

AC:

132

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

270

539

809

1078

1348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.00284

AC:

432

AN:

152376

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000865

AC:

AN:

41600

American (AMR)

AF:

0.00281

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00405

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00444

AC:

302

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00374

Hom.:

Bravo

AF:

0.00263

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.00266

AC:

323

EpiCase

AF:

0.00393

EpiControl

AF:

0.00314

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

GCC2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.031

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.63

M_CAP

Benign

0.0043

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.3

PhyloP100

0.36

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

REVEL

Benign

0.033

Sift

Benign

0.58

Sift4G

Benign

0.85

Polyphen

0.0

Vest4

0.078

MVP

0.095

MPC

0.065

ClinPred

0.0032

GERP RS

0.20

Varity_R

0.053

gMVP

0.092

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over