GCC2 p.Tyr357Cys

Variant names:

• chr2-108470399-A-G
• rs1057519387
• NM_181453.4:c.1070A>G
• GCC2 p.Tyr357Cys

Your query was ambiguous. Multiple possible variants found:

• chr2-108470399-A-G
• chr2-108470399-AT-GC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181453.4(GCC2):​c.1070A>G​(p.Tyr357Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,455,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCC2 NM_181453.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.90
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4222489).

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.1070A>G	p.Tyr357Cys	missense	Exon 6 of 23	NP_852118.2	Q8IWJ2-1
	GCC2	NM_001410194.1		c.767A>G	p.Tyr256Cys	missense	Exon 5 of 22	NP_001397123.1	A0A8I5QJB7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCC2	ENST00000309863.11	TSL:5 MANE Select	c.1070A>G	p.Tyr357Cys	missense	Exon 6 of 23	ENSP00000307939.5	Q8IWJ2-1
	GCC2	ENST00000482325.5	TSL:1	n.*847A>G		non_coding_transcript_exon	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3
	GCC2	ENST00000482325.5	TSL:1	n.*847A>G		3_prime_UTR	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248024 AF XY: 0.00000743

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455362 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724240

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00 AC: 0 AN: 85512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1107390

Other (OTH) AF: 0.00 AC: 0 AN: 60168

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Progressive sensorineural hearing impairment (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.15	T
Varity_R		0.24
gMVP		0.52
Mutation Taster		=87/13	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057519387;

hg19: chr2-109086855;