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. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. L222L) has been classified as Likely 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
• Publications: 22 publications found

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]

RIMS1 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 7

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 260500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014989.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIMS1	NM_014989.7	MANE Select	c.666A>G	p.Leu222Leu	synonymous	Exon 5 of 34	NP_055804.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIMS1	ENST00000521978.6	TSL:1 MANE Select	c.666A>G	p.Leu222Leu	synonymous	Exon 5 of 34	ENSP00000428417.1
	RIMS1	ENST00000264839.11	TSL:5	c.666A>G	p.Leu222Leu	synonymous	Exon 5 of 30	ENSP00000264839.7
	RIMS1	ENST00000697193.1		c.666A>G	p.Leu222Leu	synonymous	Exon 5 of 29	ENSP00000513179.1

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

GnomAD2 exomes AF: 0.673 AC: 167494 AN: 248746 AF XY: 0.671

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 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

African (AFR) AF: 0.808 AC: 27047 AN: 33480

American (AMR) AF: 0.671 AC: 30026 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 17065 AN: 26134

East Asian (EAS) AF: 0.869 AC: 34507 AN: 39698

South Asian (SAS) AF: 0.698 AC: 60248 AN: 86256

European-Finnish (FIN) AF: 0.613 AC: 32636 AN: 53254

Middle Eastern (MID) AF: 0.705 AC: 4066 AN: 5768

European-Non Finnish (NFE) AF: 0.629 AC: 699790 AN: 1111828

Other (OTH) AF: 0.662 AC: 39991 AN: 60364

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

African (AFR) AF: 0.801 AC: 33214 AN: 41472

American (AMR) AF: 0.681 AC: 10406 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2269 AN: 3470

East Asian (EAS) AF: 0.840 AC: 4306 AN: 5124

South Asian (SAS) AF: 0.703 AC: 3389 AN: 4818

European-Finnish (FIN) AF: 0.620 AC: 6543 AN: 10560

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42938 AN: 67906

Other (OTH) AF: 0.695 AC: 1466 AN: 2108

Alfa AF: 0.652 Hom.: 44689

Bravo AF: 0.704

Asia WGS AF: 0.795 AC: 2767 AN: 3478

EpiCase AF: 0.644

EpiControl AF: 0.637

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cone-rod dystrophy 7 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.4
DANN	Benign	0.76
PhyloP100		0.95
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2249021; hg19: chr6-72889472; COSMIC: COSV99325365; COSMIC: COSV99325365;