20-19886740-C-T

Position:

chr20-19886740-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001242581.2(RIN2):c.71C>T(p.Pro24Leu) variant causes a missense 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. 13/18 in silico tools predict 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_001242581.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.304

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.-36-2826C>T		intron_variant		ENST00000255006.12	NP_061866.1	Q8WYP3-1A1A4T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12 link	c.-36-2826C>T		intron_variant		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

GnomAD3 exomes

AF:

0.00242

AC:

355

AN:

146716

Hom.:

AF XY:

0.00233

AC XY:

183

AN XY:

78554

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 SAS exome

AF:

0.0000470

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

Gnomad4 AFR exome

AF:

0.000803

Gnomad4 AMR exome

AF:

0.000755

Gnomad4 ASJ exome

AF:

0.0000400

Gnomad4 EAS exome

AF:

0.000532

Gnomad4 SAS exome

AF:

0.000167

Gnomad4 FIN exome

AF:

0.00194

Gnomad4 NFE exome

AF:

0.00616

Gnomad4 OTH exome

AF:

0.00340

GnomAD4 genome

AF:

0.00292

AC:

444

AN:

151844

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

200

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.000869

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000776

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00124

Gnomad4 NFE

AF:

0.00539

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00425

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	RIN2: BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2017

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2019

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

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

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

gMVP

0.036

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over