8-103766524-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001348484.3(RIMS2):c.817A>G(p.Ile273Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,610,886 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (13 hom.)
• Consequence: RIMS2 NM_001348484.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.833

Genes affected

RIMS2 (HGNC:17283): (regulating synaptic membrane exocytosis 2) The protein encoded by this gene is a presynaptic protein that interacts with RAB3, a protein important for normal neurotransmitter release. The encoded protein can also bind several other synaptic proteins, including UNC-13 homolog B, ELKS/Rab6-interacting/CAST family member 1, and synaptotagmin 1. This protein is involved in synaptic membrane exocytosis. Polymorphisms in this gene have been associated with degenerative lumbar scoliosis. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003248334).
• BP6: Variant 8-103766524-A-G is Benign according to our data. Variant chr8-103766524-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 730455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00215 (327/152362) while in subpopulation NFE AF= 0.00385 (262/68032). AF 95% confidence interval is 0.00347. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIMS2	NM_001348484.3	c.817A>G	p.Ile273Val	missense_variant	6/30	ENST00000696799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIMS2	ENST00000696799.1	c.817A>G	p.Ile273Val	missense_variant	6/30		NM_001348484.3	A1

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00227 AC: 560 AN: 246986 Hom.: 1 AF XY: 0.00229 AC XY: 307 AN XY: 133968

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.000996

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00402 AC: 5868 AN: 1458524 Hom.: 13 Cov.: 30 AF XY: 0.00378 AC XY: 2746 AN XY: 725530

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.000966

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00199

Gnomad4 NFE exome AF: 0.00496

Gnomad4 OTH exome AF: 0.00322

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74510

Gnomad4 AFR AF: 0.000721

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00337 Hom.: 2

Bravo AF: 0.00213

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000520 AC: 2

ESP6500EA AF: 0.00398 AC: 33

ExAC AF: 0.00226 AC: 273

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Benign	0.92
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.12	N;.
REVEL	Benign	0.030
Sift	Benign	1.0	T;.
Sift4G	Benign	0.36	T;T
Vest4		0.14
MVP		0.20
ClinPred		0.0045	T
GERP RS		1.4
gMVP		0.18

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: rs188770151; hg19: chr8-104778752;