rs2076584

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_018993.4(RIN2):c.1818C>T(p.His606His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,596,974 control chromosomes in the GnomAD database, including 92,739 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10187 hom., cov: 33)

Exomes 𝑓: 0.33 ( 82552 hom. )

Consequence

RIN2
NM_018993.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.255

Publications

21 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 20-19990061-C-T is Benign according to our data. Variant chr20-19990061-C-T is described in ClinVar as Benign. ClinVar VariationId is 257654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.255 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.1818C>T	p.His606His	synonymous_variant	Exon 10 of 13	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
RIN2	ENST00000255006.12 link	c.1818C>T	p.His606His	synonymous_variant	Exon 10 of 13	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000440354.2 link	c.519C>T	p.His173His	synonymous_variant	Exon 5 of 8	1		ENSP00000391239.2
RIN2	ENST00000484638.1 link	n.1662C>T		non_coding_transcript_exon_variant	Exon 6 of 9	1
RIN2	ENST00000648440.1 link	c.1818C>T	p.His606His	synonymous_variant	Exon 9 of 12			ENSP00000498085.1

Frequencies

GnomAD3 genomes

AF:

0.354

AC:

53782

AN:

152008

Hom.:

10172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.387

Gnomad AMI

AF:

0.284

Gnomad AMR

AF:

0.471

Gnomad ASJ

AF:

0.330

Gnomad EAS

AF:

0.712

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.274

Gnomad NFE

AF:

0.308

Gnomad OTH

AF:

0.376

GnomAD2 exomes

AF:

0.368

AC:

82119

AN:

223160

AF XY:

0.353

show subpopulations

Gnomad AFR exome

AF:

0.384

Gnomad AMR exome

AF:

0.597

Gnomad ASJ exome

AF:

0.337

Gnomad EAS exome

AF:

0.710

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.304

Gnomad OTH exome

AF:

0.340

GnomAD4 exome

AF:

0.325

AC:

469719

AN:

1444848

Hom.:

82552

Cov.:

AF XY:

0.322

AC XY:

230974

AN XY:

716884

show subpopulations

African (AFR)

AF:

0.384

AC:

12725

AN:

33174

American (AMR)

AF:

0.579

AC:

24242

AN:

41868

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

8803

AN:

25770

East Asian (EAS)

AF:

0.743

AC:

29038

AN:

39088

South Asian (SAS)

AF:

0.247

AC:

20633

AN:

83584

European-Finnish (FIN)

AF:

0.242

AC:

12746

AN:

52576

Middle Eastern (MID)

AF:

0.258

AC:

1485

AN:

5752

European-Non Finnish (NFE)

AF:

0.308

AC:

339735

AN:

1103186

Other (OTH)

AF:

0.339

AC:

20312

AN:

59850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

15929

31858

47788

63717

79646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11434

22868

34302

45736

57170

<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:

0.354

AC:

53832

AN:

152126

Hom.:

10187

Cov.:

AF XY:

0.354

AC XY:

26341

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.386

AC:

16032

AN:

41482

American (AMR)

AF:

0.471

AC:

7213

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

1147

AN:

3472

East Asian (EAS)

AF:

0.712

AC:

3681

AN:

5170

South Asian (SAS)

AF:

0.254

AC:

1226

AN:

4828

European-Finnish (FIN)

AF:

0.231

AC:

2442

AN:

10576

Middle Eastern (MID)

AF:

0.274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.308

AC:

20954

AN:

67986

Other (OTH)

AF:

0.378

AC:

799

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1777

3554

5332

7109

8886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

526

1052

1578

2104

2630

<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:

0.335

Hom.:

37619

Bravo

AF:

0.382

Asia WGS

AF:

0.466

AC:

1616

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

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

- -

Sep 29, 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

- -

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

- -

RIN2 syndrome

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.0

(source)

DANN

Benign

0.47

PhyloP100

-0.26

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over