12-106843913-C-G

Variant names:

• chr12-106843913-C-G
• NM_001330145.2:c.1127C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001330145.2(RIC8B):​c.1127C>G​(p.Ala376Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIC8B NM_001330145.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

Genes affected

RIC8B (HGNC:25555): (RIC8 guanine nucleotide exchange factor B) Enables G-protein alpha-subunit binding activity. Acts upstream of or within regulation of G protein-coupled receptor signaling pathway. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.28492153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIC8B	NM_001330145.2	c.1127C>G	p.Ala376Gly	missense_variant	Exon 6 of 10	ENST00000392837.9	NP_001317074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIC8B	ENST00000392837.9	c.1127C>G	p.Ala376Gly	missense_variant	Exon 6 of 10	5	NM_001330145.2	ENSP00000376582.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1127C>G (p.A376G) alteration is located in exon 6 (coding exon 6) of the RIC8B gene. This alteration results from a C to G substitution at nucleotide position 1127, causing the alanine (A) at amino acid position 376 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T;T;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	.;L;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D;D;D;.
REVEL	Benign	0.11
Sift	Benign	0.18	T;T;T;.
Sift4G	Benign	0.14	T;T;T;.
Polyphen		0.27	B;B;B;.
Vest4		0.34
MutPred		0.55		Gain of catalytic residue at R375 (P = 0.0012);Gain of catalytic residue at R375 (P = 0.0012);.;Gain of catalytic residue at R375 (P = 0.0012);
MVP		0.22
MPC		0.72
ClinPred		0.53	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.19

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-107237691;