chr20-19886680-C-G

Variant names:

• chr20-19886680-C-G
• rs1274205552
• NM_018993.4:c.-36-2886C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018993.4(RIN2):​c.-36-2886C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000441 in 1,359,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.589
• Publications: 0 publications found

Genes affected

RIN2 (HGNC:18750): (Ras and Rab interactor 2) The RAB5 protein is a small GTPase involved in membrane trafficking in the early endocytic pathway. The protein encoded by this gene binds the GTP-bound form of the RAB5 protein preferentially over the GDP-bound form, and functions as a guanine nucleotide exchange factor for RAB5. The encoded protein is found primarily as a tetramer in the cytoplasm and does not bind other members of the RAB family. Mutations in this gene cause macrocephaly alopecia cutis laxa and scoliosis (MACS) syndrome, an elastic tissue disorder, as well as the related connective tissue disorder, RIN2 syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2011]

RIN2 Gene-Disease associations (from GenCC):

• RIN2 syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

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 (BayesDel_addAF=-0.0319729).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2886C>G		intron_variant	Intron 2 of 12	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2886C>G		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000673 AC: 1 AN: 148678 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000441 AC: 6 AN: 1359540 Hom.: 0 Cov.: 29 AF XY: 0.00000298 AC XY: 2 AN XY: 671854

African (AFR) AF: 0.00 AC: 0 AN: 30660

American (AMR) AF: 0.00 AC: 0 AN: 35258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24498

East Asian (EAS) AF: 0.00 AC: 0 AN: 34680

South Asian (SAS) AF: 0.00 AC: 0 AN: 78488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00000478 AC: 5 AN: 1046746

Other (OTH) AF: 0.0000178 AC: 1 AN: 56334

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RIN2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001242581.1, and corresponds to NM_018993.3:c.-2922C>G in the primary transcript. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with RIN2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change results in a premature translational stop signal in the RIN2 gene (p.Ser4*). However, it is currently unclear if variants that occur in this region of the gene cause disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	2.2
DANN	Benign	0.96
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.061	N
PhyloP100		-0.59
Vest4		0.17
GERP RS		-4.5
PromoterAI		0.033	Neutral
Mutation Taster		=149/51	disease causing (fs/PTC)

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: rs1274205552; hg19: chr20-19867324;