dbSNP rs141520578: GCC2:p.His124Arg (chr2-108469700-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 3042982.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCC2	NM_181453.4 link	c.371A>G	p.His124Arg	missense_variant	Exon 6 of 23	ENST00000309863.11	NP_852118.2	Q8IWJ2-1B3KR21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCC2	ENST00000309863.11 link	c.371A>G	p.His124Arg	missense_variant	Exon 6 of 23	5	NM_181453.4	ENSP00000307939.5		Q8IWJ2-1

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

GnomAD3 exomes

AF:

0.00257

AC:

642

AN:

249978

Hom.:

AF XY:

0.00234

AC XY:

317

AN XY:

135214

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 SAS exome

AF:

0.0000330

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

Gnomad4 AFR exome

AF:

0.000719

Gnomad4 AMR exome

AF:

0.000853

Gnomad4 ASJ exome

AF:

0.000728

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00348

Gnomad4 NFE exome

AF:

0.00486

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.00284

AC:

432

AN:

152376

Hom.:

Cov.:

AF XY:

0.00295

AC XY:

220

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000865

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00405

Gnomad4 NFE

AF:

0.00444

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00392

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

GCC2-related disorder

Benign:1

Feb 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.031

T;T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.3

L;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.033

Sift

Benign

0.58

T;T;T

Sift4G

Benign

0.85

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.078

MVP

0.095

MPC

0.065

ClinPred

0.0032

GERP RS

0.20

Varity_R

0.053

gMVP

0.092

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