rs2249021

Variant names:

• chr6-72179769-A-G
• rs2249021
• NM_014989.7:c.666A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-72179769-A-G
• chr6-72179769-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014989.7(RIMS1):​c.666A>G​(p.Leu222Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.651 in 1,613,444 control chromosomes in the GnomAD database, including 344,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36980 hom., cov: 30)
  • Exomes 𝑓: 0.65 (308018 hom.)
• Consequence: RIMS1 NM_014989.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.950

Genes affected

RIMS1 (HGNC:17282): (regulating synaptic membrane exocytosis 1) The protein encoded by this gene is a RAS gene superfamily member that regulates synaptic vesicle exocytosis. This gene also plays a role in the regulation of voltage-gated calcium channels during neurotransmitter and insulin release. Mutations have suggested a role cognition and have been identified as the cause of cone-rod dystrophy type 7. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 6-72179769-A-G is Benign according to our data. Variant chr6-72179769-A-G is described in ClinVar as [Benign]. Clinvar id is 260500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-72179769-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.95 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.819 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIMS1	NM_014989.7	c.666A>G	p.Leu222Leu	synonymous_variant	Exon 5 of 34	ENST00000521978.6	NP_055804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIMS1	ENST00000521978.6	c.666A>G	p.Leu222Leu	synonymous_variant	Exon 5 of 34	1	NM_014989.7	ENSP00000428417.1

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105227 AN: 151820 Hom.: 36938 Cov.: 30

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.620

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.693

GnomAD3 exomes AF: 0.673 AC: 167494 AN: 248746 Hom.: 56770 AF XY: 0.671 AC XY: 90652 AN XY: 135016

Gnomad AFR exome AF: 0.809

Gnomad AMR exome AF: 0.667

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.837

Gnomad SAS exome AF: 0.701

Gnomad FIN exome AF: 0.615

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.647 AC: 945376 AN: 1461506 Hom.: 308018 Cov.: 58 AF XY: 0.648 AC XY: 471203 AN XY: 727020

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.671

Gnomad4 ASJ exome AF: 0.653

Gnomad4 EAS exome AF: 0.869

Gnomad4 SAS exome AF: 0.698

Gnomad4 FIN exome AF: 0.613

Gnomad4 NFE exome AF: 0.629

Gnomad4 OTH exome AF: 0.662

GnomAD4 genome AF: 0.693 AC: 105334 AN: 151938 Hom.: 36980 Cov.: 30 AF XY: 0.692 AC XY: 51368 AN XY: 74282

Gnomad4 AFR AF: 0.801

Gnomad4 AMR AF: 0.681

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.840

Gnomad4 SAS AF: 0.703

Gnomad4 FIN AF: 0.620

Gnomad4 NFE AF: 0.632

Gnomad4 OTH AF: 0.695

Alfa AF: 0.645 Hom.: 33895

Bravo AF: 0.704

Asia WGS AF: 0.795 AC: 2767 AN: 3478

EpiCase AF: 0.644

EpiControl AF: 0.637

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone-rod dystrophy 7 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Apr 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.4
DANN	Benign	0.76

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: rs2249021; hg19: chr6-72889472;