8-103885700-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001348484.3(RIMS2):c.1233G>A(p.Arg411=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,613,030 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (22 hom.)
• Consequence: RIMS2 NM_001348484.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.166

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 8-103885700-G-A is Benign according to our data. Variant chr8-103885700-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 711041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-103885700-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.166 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0025 (380/151982) while in subpopulation NFE AF= 0.00427 (290/67886). AF 95% confidence interval is 0.00387. There are 1 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIMS2	NM_001348484.3	c.1233G>A	p.Arg411=	synonymous_variant	7/30	ENST00000696799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIMS2	ENST00000696799.1	c.1233G>A	p.Arg411=	synonymous_variant	7/30		NM_001348484.3	A1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 381 AN: 151864 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00427

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00249 AC: 619 AN: 248600 Hom.: 2 AF XY: 0.00252 AC XY: 340 AN XY: 134898

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00867

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00205

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00411 AC: 6008 AN: 1461048 Hom.: 22 Cov.: 33 AF XY: 0.00407 AC XY: 2955 AN XY: 726854

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00468

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00250 AC: 380 AN: 151982 Hom.: 1 Cov.: 32 AF XY: 0.00225 AC XY: 167 AN XY: 74264

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00427

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00304 Hom.: 0

Bravo AF: 0.00240

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	RIMS2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	7.2
Dann	Benign	0.55

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: rs202004651; hg19: chr8-104897928;