Genetic Variant RIN2:p.Ser322Asn (chr20-19974990-G-A) – ACMG Classification: Benign (-20 pts)

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.965G>A(p.Ser322Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000951 in 1,336,970 control chromosomes in the GnomAD database, including 11 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., cov: 31)

Exomes 𝑓: 0.00051 ( 9 hom. )

Consequence

RIN2
NM_018993.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.65

Publications

0 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=0.005121976).

BP6

Variant 20-19974990-G-A is Benign according to our data. Variant chr20-19974990-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00519 (652/125686) while in subpopulation AFR AF = 0.0184 (620/33732). AF 95% confidence interval is 0.0172. There are 2 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.965G>A	p.Ser322Asn	missense	Exon 9 of 13	NP_061866.1
RIN2	NM_001242581.2		c.1112G>A	p.Ser371Asn	missense	Exon 8 of 12	NP_001229510.1
RIN2	NM_001378238.1		c.347G>A	p.Ser116Asn	missense	Exon 8 of 12	NP_001365167.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIN2	ENST00000255006.12	TSL:2 MANE Select	c.965G>A	p.Ser322Asn	missense	Exon 9 of 13	ENSP00000255006.7
RIN2	ENST00000484638.1	TSL:1	n.809G>A		non_coding_transcript_exon	Exon 5 of 9
RIN2	ENST00000440354.2	TSL:1	c.463+14179G>A		intron	N/A	ENSP00000391239.2

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

651

AN:

125644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0184

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00186

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000486

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00112

AC:

277

AN:

247700

AF XY:

0.000883

show subpopulations

Gnomad AFR exome

AF:

0.0161

Gnomad AMR exome

AF:

0.000697

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000511

AC:

619

AN:

1211284

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

274

AN XY:

600788

show subpopulations

African (AFR)

AF:

0.0182

AC:

484

AN:

26578

American (AMR)

AF:

0.000957

AC:

AN:

37632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17298

East Asian (EAS)

AF:

0.00

AC:

AN:

18312

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32532

Middle Eastern (MID)

AF:

0.000443

AC:

AN:

4518

European-Non Finnish (NFE)

AF:

0.0000518

AC:

AN:

946462

Other (OTH)

AF:

0.00106

AC:

AN:

44314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00519

AC:

652

AN:

125686

Hom.:

Cov.:

AF XY:

0.00516

AC XY:

306

AN XY:

59276

show subpopulations

African (AFR)

AF:

0.0184

AC:

620

AN:

33732

American (AMR)

AF:

0.00186

AC:

AN:

10744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3244

East Asian (EAS)

AF:

0.00

AC:

AN:

3622

South Asian (SAS)

AF:

0.00

AC:

AN:

3480

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

61762

Other (OTH)

AF:

0.00524

AC:

AN:

1718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

116

145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00449

Hom.:

Bravo

AF:

0.00505

ESP6500AA

AF:

0.0162

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00145

AC:

175

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Dec 28, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

Eigen

Benign

-0.027

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.6

PhyloP100

2.7

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.97

REVEL

Benign

0.054

Sift

Benign

0.11

Sift4G

Benign

0.39

Polyphen

0.0060

Vest4

0.22

MVP

0.24

MPC

0.19

ClinPred

0.0074

GERP RS

5.6

Varity_R

0.12

gMVP

0.24

Mutation Taster

=97/3

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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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