11-209908-C-T

Variant names:

• chr11-209908-C-T
• rs202016084
• NM_001286134.2:c.634C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001286134.2(RIC8A):​c.634C>T​(p.Leu212Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. L212I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIC8A NM_001286134.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.521
• Publications: 0 publications found

Genes affected

RIC8A (HGNC:29550): (RIC8 guanine nucleotide exchange factor A) Predicted to enable G-protein alpha-subunit binding activity; GTPase activator activity; and guanyl-nucleotide exchange factor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Predicted to act upstream of or within several processes, including basement membrane organization; gastrulation; and visual learning. Predicted to be located in membrane. Predicted to be active in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06999639).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286134.2. 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
	RIC8A	NM_001286134.2	MANE Select	c.634C>T	p.Leu212Phe	missense	Exon 3 of 10	NP_001273063.1	Q9NPQ8-1
	RIC8A	NM_021932.6		c.634C>T	p.Leu212Phe	missense	Exon 3 of 10	NP_068751.4
	RIC8A	NM_001386941.1		c.646C>T	p.Leu216Phe	missense	Exon 3 of 10	NP_001373870.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIC8A	ENST00000526104.6	TSL:1 MANE Select	c.634C>T	p.Leu212Phe	missense	Exon 3 of 10	ENSP00000432008.1	Q9NPQ8-1
	RIC8A	ENST00000325207.9	TSL:1	c.634C>T	p.Leu212Phe	missense	Exon 3 of 10	ENSP00000325941.5	Q9NPQ8-3
	RIC8A	ENST00000527696.5	TSL:1	c.616C>T	p.Leu206Phe	missense	Exon 1 of 8	ENSP00000434833.1	Q9NPQ8-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456250 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724670

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.8
DANN	Benign	0.95
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.52
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.038
Sift	Benign	0.093	T
Sift4G	Benign	0.31	T
Polyphen		0.0040	B
Vest4		0.063
MutPred		0.49		Loss of phosphorylation at S215 (P = 0.1831)
MVP		0.47
MPC		0.28
ClinPred		0.058	T
GERP RS		-3.1
PromoterAI		0.0096	Neutral
Varity_R		0.13
gMVP		0.073
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202016084; hg19: chr11-209908;