8-103766399-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001348484.3(RIMS2):c.692C>T(p.Thr231Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000769 in 1,613,780 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom.)
• Consequence: RIMS2 NM_001348484.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.73

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049807727).
• BP6: Variant 8-103766399-C-T is Benign according to our data. Variant chr8-103766399-C-T is described in ClinVar as [Benign]. Clinvar id is 720429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0043 (655/152200) while in subpopulation AFR AF= 0.0148 (614/41516). AF 95% confidence interval is 0.0138. There are 6 homozygotes in gnomad4. There are 320 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIMS2	NM_001348484.3	c.692C>T	p.Thr231Ile	missense_variant	6/30	ENST00000696799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIMS2	ENST00000696799.1	c.692C>T	p.Thr231Ile	missense_variant	6/30		NM_001348484.3	A1

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 654 AN: 152082 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00107 AC: 267 AN: 249142 Hom.: 0 AF XY: 0.000873 AC XY: 118 AN XY: 135148

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000401 AC: 586 AN: 1461580 Hom.: 1 Cov.: 31 AF XY: 0.000366 AC XY: 266 AN XY: 727078

Gnomad4 AFR exome AF: 0.0154

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.00430 AC: 655 AN: 152200 Hom.: 6 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74402

Gnomad4 AFR AF: 0.0148

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000579 Hom.: 0

Bravo AF: 0.00498

ESP6500AA AF: 0.0146 AC: 56

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00133 AC: 161

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.035
Sift	Uncertain	0.018	D;.
Sift4G	Uncertain	0.023	D;D
Vest4		0.12
MVP		0.13
ClinPred		0.015	T
GERP RS		4.3
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs61729653; hg19: chr8-104778627; COSMIC: COSV68113258; COSMIC: COSV68113258;