Genetic Variant RIMS2:p.Lys48Asn (chr8-103501030-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001348484.3(RIMS2):c.144G>T(p.Lys48Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RIMS2
NM_001348484.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

Publications

0 publications found

Variant links:

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]

RIMS2 Gene-Disease associations (from GenCC):

cone-rod synaptic disorder syndrome, congenital nonprogressive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
cone-rod synaptic disorder, congenital nonprogressive
Inheritance: AR Classification: STRONG Submitted by: Franklin by Genoox

RIMS2 links:

ENSG00000285982 (HGNC:):

ENSG00000285982 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3013733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIMS2	NM_001348484.3 link	c.144G>T	p.Lys48Asn	missense_variant	Exon 1 of 30	ENST00000696799.1	NP_001335413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIMS2	ENST00000696799.1 link	c.144G>T	p.Lys48Asn	missense_variant	Exon 1 of 30		NM_001348484.3	ENSP00000512879.1		A0A8Q3SIU4
ENSG00000285982	ENST00000649416.1 link	c.-232+766C>A		intron_variant	Intron 1 of 8			ENSP00000496817.1		A0A3B3IRK5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.144G>T (p.K48N) alteration is located in exon 1 (coding exon 1) of the RIMS2 gene. This alteration results from a G to T substitution at nucleotide position 144, causing the lysine (K) at amino acid position 48 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.61

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.9

M;.

PhyloP100

3.3

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.091

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0090

D;D

Vest4

0.43

MutPred

0.26

Loss of ubiquitination at K48 (P = 0.0077);Loss of ubiquitination at K48 (P = 0.0077);

MVP

0.55

ClinPred

0.92

GERP RS

3.8

PromoterAI

-0.047

Neutral

(source)

gMVP

0.31

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over