20-19975029-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018993.4(RIN2):c.1004C>G(p.Pro335Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,490 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

RIN2
NM_018993.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 7.58

Publications

7 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010970145).

BP6

Variant 20-19975029-C-G is Benign according to our data. Variant chr20-19975029-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436539.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000966 (147/152230) while in subpopulation AMR AF = 0.00235 (36/15302). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.1004C>G	p.Pro335Arg	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.1004C>G	p.Pro335Arg	missense_variant	Exon 9 of 13	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000484638.1 link	n.848C>G		non_coding_transcript_exon_variant	Exon 5 of 9	1
RIN2	ENST00000440354.2 link	c.463+14218C>G		intron_variant	Intron 4 of 7	1		ENSP00000391239.2	E7EPJ1
RIN2	ENST00000648440.1 link	c.1004C>G	p.Pro335Arg	missense_variant	Exon 8 of 12			ENSP00000498085.1	Q8WYP3-1

Frequencies

GnomAD3 genomes

AF:

0.000966

AC:

147

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00146

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000937

AC:

232

AN:

247546

AF XY:

0.000920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000932

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00116

AC:

1691

AN:

1461260

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

821

AN XY:

726888

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.00273

AC:

122

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000132

AC:

AN:

52958

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00133

AC:

1480

AN:

1111866

Other (OTH)

AF:

0.00128

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

106

213

319

426

532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<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:

0.000966

AC:

147

AN:

152230

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41546

American (AMR)

AF:

0.00235

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00146

AC:

AN:

68004

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00107

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00131

AC:

ExAC

AF:

0.000885

AC:

107

EpiCase

AF:

0.00109

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 23, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1004C>G (p.P335R) alteration is located in exon 7 (coding exon 7) of the RIN2 gene. This alteration results from a C to G substitution at nucleotide position 1004, causing the proline (P) at amino acid position 335 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

RIN2-related disorder

Benign:1

Dec 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

7.6

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.8

.;D

REVEL

Benign

0.25

Sift

Uncertain

0.0020

.;D

Sift4G

Uncertain

0.034

.;D

Polyphen

1.0

D;.

Vest4

0.55

MVP

0.56

MPC

0.73

ClinPred

0.13

GERP RS

5.6

Varity_R

0.40

gMVP

0.38

Mutation Taster

=29/71

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

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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