NM_181453.4:c.974T>C

Variant names:

• chr2-108470303-T-C
• rs1397845853
• NM_181453.4:c.974T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181453.4(GCC2):​c.974T>C​(p.Phe325Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F325C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCC2 NM_181453.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04912737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCC2	NM_181453.4	c.974T>C	p.Phe325Ser	missense_variant	Exon 6 of 23	ENST00000309863.11	NP_852118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCC2	ENST00000309863.11	c.974T>C	p.Phe325Ser	missense_variant	Exon 6 of 23	5	NM_181453.4	ENSP00000307939.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.3
DANN	Benign	0.61
DEOGEN2	Benign	0.022	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.23	N;N
REVEL	Benign	0.043
Sift	Benign	0.45	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.34		Gain of disorder (P = 9e-04);.;
MVP		0.085
MPC		0.092
ClinPred		0.036	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.037
gMVP		0.077

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: rs1397845853; hg19: chr2-109086759;