20-19970890-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_018993.4(RIN2):c.589T>A(p.Ser197Thr) variant causes a missense change. The variant allele was found at a frequency of 0.153 in 1,612,492 control chromosomes in the GnomAD database, including 19,608 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S197L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 1765 hom., cov: 32)

Exomes 𝑓: 0.15 ( 17843 hom. )

Consequence

RIN2
NM_018993.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.88

Publications

35 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=0.0010179281).

BP6

Variant 20-19970890-T-A is Benign according to our data. Variant chr20-19970890-T-A is described in ClinVar as Benign. ClinVar VariationId is 257655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018993.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIN2	NM_018993.4	MANE Select	c.589T>A	p.Ser197Thr	missense	Exon 8 of 13	NP_061866.1
RIN2	NM_001242581.2		c.736T>A	p.Ser246Thr	missense	Exon 7 of 12	NP_001229510.1
RIN2	NM_001378238.1		c.-30T>A		5_prime_UTR	Exon 7 of 12	NP_001365167.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIN2	ENST00000255006.12	TSL:2 MANE Select	c.589T>A	p.Ser197Thr	missense	Exon 8 of 13	ENSP00000255006.7
RIN2	ENST00000484638.1	TSL:1	n.433T>A		non_coding_transcript_exon	Exon 4 of 9
RIN2	ENST00000440354.2	TSL:1	c.463+10079T>A		intron	N/A	ENSP00000391239.2

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22859

AN:

152048

Hom.:

1767

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.151

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.272

Gnomad SAS

AF:

0.0754

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.147

Gnomad OTH

AF:

0.157

GnomAD2 exomes

AF:

0.152

AC:

37812

AN:

247982

AF XY:

0.149

show subpopulations

Gnomad AFR exome

AF:

0.146

Gnomad AMR exome

AF:

0.169

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.285

Gnomad FIN exome

AF:

0.130

Gnomad NFE exome

AF:

0.147

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.153

AC:

223428

AN:

1460326

Hom.:

17843

Cov.:

AF XY:

0.151

AC XY:

109484

AN XY:

726396

show subpopulations

African (AFR)

AF:

0.158

AC:

5293

AN:

33462

American (AMR)

AF:

0.165

AC:

7337

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

5008

AN:

26112

East Asian (EAS)

AF:

0.234

AC:

9297

AN:

39672

South Asian (SAS)

AF:

0.0825

AC:

7101

AN:

86072

European-Finnish (FIN)

AF:

0.132

AC:

7020

AN:

53362

Middle Eastern (MID)

AF:

0.169

AC:

975

AN:

5768

European-Non Finnish (NFE)

AF:

0.155

AC:

171805

AN:

1110952

Other (OTH)

AF:

0.159

AC:

9592

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

8923

17846

26770

35693

44616

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6312

12624

18936

25248

31560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.150

AC:

22866

AN:

152166

Hom.:

1765

Cov.:

AF XY:

0.150

AC XY:

11163

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.151

AC:

6270

AN:

41502

American (AMR)

AF:

0.151

AC:

2309

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

675

AN:

3472

East Asian (EAS)

AF:

0.272

AC:

1406

AN:

5172

South Asian (SAS)

AF:

0.0754

AC:

364

AN:

4826

European-Finnish (FIN)

AF:

0.136

AC:

1437

AN:

10588

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.147

AC:

9980

AN:

68002

Other (OTH)

AF:

0.156

AC:

330

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1022

2045

3067

4090

5112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.154

Hom.:

1425

Bravo

AF:

0.158

TwinsUK

AF:

0.156

AC:

577

ALSPAC

AF:

0.157

AC:

606

ESP6500AA

AF:

0.141

AC:

547

ESP6500EA

AF:

0.152

AC:

1255

ExAC

AF:

0.149

AC:

18017

Asia WGS

AF:

0.143

AC:

495

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 11, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.020

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

6.9

PrimateAI

Benign

0.43

PROVEAN

Benign

0.26

REVEL

Benign

0.12

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.014

MPC

0.17

ClinPred

0.011

GERP RS

4.6

Varity_R

0.22

gMVP

0.30

Mutation Taster

=93/7

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over