2-108470566-A-G

Variant names:

• chr2-108470566-A-G
• rs1681142708
• NM_181453.4:c.1237A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181453.4(GCC2):​c.1237A>G​(p.Lys413Glu) 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 1,455,176 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 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: 0.528
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037567347).

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.1237A>G	p.Lys413Glu	missense	Exon 6 of 23	NP_852118.2	Q8IWJ2-1
	GCC2	NM_001410194.1		c.934A>G	p.Lys312Glu	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.1237A>G	p.Lys413Glu	missense	Exon 6 of 23	ENSP00000307939.5	Q8IWJ2-1
	GCC2	ENST00000482325.5	TSL:1	n.*1014A>G		non_coding_transcript_exon	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3
	GCC2	ENST00000482325.5	TSL:1	n.*1014A>G		3_prime_UTR	Exon 5 of 22	ENSP00000419969.1	Q8IWJ2-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455176 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 723762

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32956

American (AMR) AF: 0.00 AC: 0 AN: 43624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 84700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109322

Other (OTH) AF: 0.00 AC: 0 AN: 60074

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.063
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.2
DANN	Benign	0.42
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.53
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.034
Sift	Benign	0.32	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.22		Loss of methylation at K413 (P = 0.0091)
MVP		0.16
MPC		0.074
ClinPred		0.060	T
GERP RS		0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.049
Mutation Taster		=91/9	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: rs1681142708; hg19: chr2-109087022;