chr20-19886740-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018993.4(RIN2):c.-36-2826C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,545,556 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 29)

Exomes 𝑓: 0.0050 ( 41 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.304

Publications

3 publications found

Variant links:

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)

RIN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043200552).

BP6

Variant 20-19886740-C-T is Benign according to our data. Variant chr20-19886740-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 444566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00292 (444/151844) while in subpopulation NFE AF = 0.00539 (366/67964). AF 95% confidence interval is 0.00493. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.-36-2826C>T		intron_variant	Intron 2 of 12	ENST00000255006.12	NP_061866.1	Q8WYP3-1A1A4T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12 link	c.-36-2826C>T		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7		Q8WYP3-1

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

444

AN:

151728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000872

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00242

AC:

355

AN:

146716

AF XY:

0.00233

show subpopulations

Gnomad AFR exome

AF:

0.000427

Gnomad AMR exome

AF:

0.000593

Gnomad ASJ exome

AF:

0.000121

Gnomad EAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00177

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00185

GnomAD4 exome

AF:

0.00503

AC:

7015

AN:

1393712

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

3378

AN XY:

687434

show subpopulations

African (AFR)

AF:

0.000803

AC:

AN:

31146

American (AMR)

AF:

0.000755

AC:

AN:

34450

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

25008

East Asian (EAS)

AF:

0.000532

AC:

AN:

35722

South Asian (SAS)

AF:

0.000167

AC:

AN:

78050

European-Finnish (FIN)

AF:

0.00194

AC:

AN:

48374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00616

AC:

6640

AN:

1077322

Other (OTH)

AF:

0.00340

AC:

197

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

296

593

889

1186

1482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00292

AC:

444

AN:

151844

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

200

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.000869

AC:

AN:

41426

American (AMR)

AF:

0.00138

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000776

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00539

AC:

366

AN:

67964

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00358

Hom.:

Bravo

AF:

0.00294

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00415

AC:

ExAC

AF:

0.00118

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RIN2: BS2 -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 13, 2017

GeneDx

Significance:Likely 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. -

RIN2-related disorder

Benign:1

May 31, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.4

(source)

DANN

Benign

0.85

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.45

M_CAP

Benign

0.021

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

PhyloP100

-0.30

PrimateAI

Benign

0.23

PROVEAN

Benign

0.13

REVEL

Benign

0.0080

Sift

Pathogenic

0.0

Vest4

0.076

MVP

0.17

MPC

0.20

ClinPred

0.028

GERP RS

-7.0

PromoterAI

-0.19

Neutral

(source)

gMVP

0.036

Mutation Taster

=100/0

polymorphism

(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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chr20-19886740-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over