NM_001330145.2:c.1243C>T

Variant names:

• chr12-106851531-C-T
• rs144307297
• NM_001330145.2:c.1243C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001330145.2(RIC8B):​c.1243C>T​(p.His415Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RIC8B NM_001330145.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 2 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816
• BS2: High AC in GnomAdExome4 at 13 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.1243C>T	p.His415Tyr	missense	Exon 7 of 10	NP_001317074.1	B7WPL0
	RIC8B	NM_001351361.2		c.1219C>T	p.His407Tyr	missense	Exon 8 of 11	NP_001338290.1
	RIC8B	NM_001330146.2		c.1195C>T	p.His399Tyr	missense	Exon 6 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.1243C>T	p.His415Tyr	missense	Exon 7 of 10	ENSP00000376582.4	B7WPL0
	RIC8B	ENST00000392839.6	TSL:1	c.1243C>T	p.His415Tyr	missense	Exon 7 of 9	ENSP00000376583.2	Q9NVN3-5
	RIC8B	ENST00000355478.6	TSL:1	c.1123C>T	p.His375Tyr	missense	Exon 8 of 12	ENSP00000347662.2	Q9NVN3-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251340 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461284 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111850

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74286

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.29
MPC		1.7
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.59
gMVP		0.72
Mutation Taster		=27/73	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: rs144307297; hg19: chr12-107245309;