chr20-19886282-G-A

Variant names:

• chr20-19886282-G-A
• rs75113125
• NM_018993.4:c.-36-3284G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018993.4(RIN2):​c.-36-3284G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 152,240 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.039 (145 hom., cov: 32)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.41
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 20-19886282-G-A is Benign according to our data. Variant chr20-19886282-G-A is described in ClinVar as [Benign]. Clinvar id is 669475.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-3284G>A		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.-36-3284G>A		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000432334.2	n.537-3284G>A		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-3284G>A		intron_variant	Intron 3 of 3
RIN2	ENST00000648440.1	c.-535G>A		upstream_gene_variant				ENSP00000498085.1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5932 AN: 152122 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.0677

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0245

Gnomad OTH AF: 0.0503

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0390 AC: 5930 AN: 152240 Hom.: 145 Cov.: 32 AF XY: 0.0395 AC XY: 2942 AN XY: 74432

African (AFR) AF: 0.0518 AC: 2152 AN: 41538

American (AMR) AF: 0.0429 AC: 656 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 315 AN: 3470

East Asian (EAS) AF: 0.0668 AC: 346 AN: 5176

South Asian (SAS) AF: 0.0866 AC: 417 AN: 4816

European-Finnish (FIN) AF: 0.0235 AC: 250 AN: 10618

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0245 AC: 1666 AN: 68004

Other (OTH) AF: 0.0507 AC: 107 AN: 2110

Alfa AF: 0.0322 Hom.: 171

Bravo AF: 0.0412

Asia WGS AF: 0.0710 AC: 245 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.029
DANN	Benign	0.63
PhyloP100		-3.4
PromoterAI		0.014	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75113125; hg19: chr20-19866926;