12-106815243-C-T

Variant names:

• chr12-106815243-C-T
• rs141759924
• NM_001330145.2:c.680C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001330145.2(RIC8B):​c.680C>T​(p.Ala227Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,613,978 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: RIC8B NM_001330145.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06936085).
• BS2: High AC in GnomAd4 at 38 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330145.2. 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
	RIC8B	NM_001330145.2	MANE Select	c.680C>T	p.Ala227Val	missense	Exon 3 of 10	NP_001317074.1	B7WPL0
	RIC8B	NM_001351361.2		c.656C>T	p.Ala219Val	missense	Exon 4 of 11	NP_001338290.1
	RIC8B	NM_001330146.2		c.632C>T	p.Ala211Val	missense	Exon 2 of 9	NP_001317075.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIC8B	ENST00000392837.9	TSL:5 MANE Select	c.680C>T	p.Ala227Val	missense	Exon 3 of 10	ENSP00000376582.4	B7WPL0
	RIC8B	ENST00000392839.6	TSL:1	c.680C>T	p.Ala227Val	missense	Exon 3 of 9	ENSP00000376583.2	Q9NVN3-5
	RIC8B	ENST00000355478.6	TSL:1	c.560C>T	p.Ala187Val	missense	Exon 4 of 12	ENSP00000347662.2	Q9NVN3-3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000957 AC: 24 AN: 250796 AF XY: 0.0000811

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727198

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111966

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74346

African (AFR) AF: 0.000893 AC: 37 AN: 41426

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000355

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.30
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.99	L
PhyloP100		4.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.20
Sift	Benign	0.33	T
Sift4G	Benign	0.93	T
Polyphen		0.91	P
Vest4		0.39
MVP		0.26
MPC		0.78
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.063
gMVP		0.51
Mutation Taster		=48/52	disease causing

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: rs141759924; hg19: chr12-107209021;