rs1057519387

Positions:

• chr2-108470399-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCC2	NM_181453.4	c.1070A>G	p.Tyr357Cys	missense_variant	6/23	ENST00000309863.11	NP_852118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCC2	ENST00000309863.11	c.1070A>G	p.Tyr357Cys	missense_variant	6/23	5	NM_181453.4	ENSP00000307939	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248024 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134564

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: 0.00000889

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

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive sensorineural hearing impairment Uncertain:1

Uncertain significance, no assertion criteria provided

research

Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)

Sep 03, 2016

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Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.15	T;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.36		Loss of phosphorylation at Y357 (P = 0.027);.;
MVP		0.54
MPC		0.39
ClinPred		0.75	D
GERP RS		5.5
Varity_R		0.24
gMVP		0.52

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

Other links and lift over

dbSNP: rs1057519387; hg19: chr2-109086855;