rs374058245

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_018993.4(RIN2):c.923C>A(p.Pro308Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000985 in 1,603,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P308R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

RIN2
NM_018993.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 3.71

Publications

2 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14283267).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000205 (31/151488) while in subpopulation EAS AF = 0.00078 (4/5126). AF 95% confidence interval is 0.000355. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.923C>A	p.Pro308Gln	missense_variant	Exon 9 of 13	ENST00000255006.12	NP_061866.1	Q8WYP3-1A1A4T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIN2	ENST00000255006.12 link	c.923C>A	p.Pro308Gln	missense_variant	Exon 9 of 13	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000484638.1 link	n.767C>A		non_coding_transcript_exon_variant	Exon 5 of 9	1
RIN2	ENST00000440354.2 link	c.463+14137C>A		intron_variant	Intron 4 of 7	1		ENSP00000391239.2	E7EPJ1
RIN2	ENST00000648440.1 link	c.923C>A	p.Pro308Gln	missense_variant	Exon 8 of 12			ENSP00000498085.1	Q8WYP3-1

Frequencies

GnomAD3 genomes

AF:

0.000205

AC:

AN:

151372

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000219

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000779

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000166

AC:

AN:

247140

AF XY:

0.000164

show subpopulations

Gnomad AFR exome

AF:

0.000197

Gnomad AMR exome

AF:

0.000498

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.000281

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000875

AC:

127

AN:

1452176

Hom.:

Cov.:

AF XY:

0.0000982

AC XY:

AN XY:

722778

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33294

American (AMR)

AF:

0.000493

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26044

East Asian (EAS)

AF:

0.000101

AC:

AN:

39622

South Asian (SAS)

AF:

0.000116

AC:

AN:

86072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53052

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000707

AC:

AN:

1103638

Other (OTH)

AF:

0.000117

AC:

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.595

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000205

AC:

AN:

151488

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74116

show subpopulations

African (AFR)

AF:

0.000218

AC:

AN:

41290

American (AMR)

AF:

0.000656

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000780

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67666

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.598

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000364

Hom.:

Bravo

AF:

0.000257

ExAC

AF:

0.000166

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 23, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RIN2-related disorder

Uncertain:1

Mar 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The RIN2 c.1070C>A variant is predicted to result in the amino acid substitution p.Pro357Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Jun 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.923C>A (p.P308Q) alteration is located in exon 7 (coding exon 7) of the RIN2 gene. This alteration results from a C to A substitution at nucleotide position 923, causing the proline (P) at amino acid position 308 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 308 of the RIN2 protein (p.Pro308Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 212056). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

RIN2 syndrome

Uncertain:1

Jul 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

3.7

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.2

.;D

REVEL

Benign

0.20

Sift

Uncertain

0.0020

.;D

Sift4G

Benign

0.068

.;T

Polyphen

1.0

D;.

Vest4

0.58

MutPred

0.25

Loss of glycosylation at P308 (P = 4e-04);.;

MVP

0.60

MPC

0.72

ClinPred

0.36

GERP RS

5.6

Varity_R

0.16

gMVP

0.55

Mutation Taster

=35/65

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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