chr2-108470305-G-T

Variant names:

• chr2-108470305-G-T
• rs1681126066
• NM_181453.4:c.976G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181453.4(GCC2):​c.976G>T​(p.Val326Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,346 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GCC2 NM_181453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.831
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06839186).

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.976G>T	p.Val326Leu	missense	Exon 6 of 23	NP_852118.2	Q8IWJ2-1
	GCC2	NM_001410194.1		c.673G>T	p.Val225Leu	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.976G>T	p.Val326Leu	missense	Exon 6 of 23	ENSP00000307939.5	Q8IWJ2-1
	GCC2	ENST00000482325.5	TSL:1	n.*753G>T		non_coding_transcript_exon	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3
	GCC2	ENST00000482325.5	TSL:1	n.*753G>T		3_prime_UTR	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460346 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726452

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 85838

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111386

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.4
DANN	Benign	0.83
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.83
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.023
Sift	Benign	0.14	T
Sift4G	Benign	0.49	T
Polyphen		0.043	B
Vest4		0.18
MutPred		0.14		Gain of disorder (P = 0.1603)
MVP		0.18
MPC		0.069
ClinPred		0.048	T
GERP RS		-0.19
Varity_R		0.032
gMVP		0.13
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs1681126066; hg19: chr2-109086761;