Genetic Variant RIN2:c.-36-2826C>T (chr20-19886740-C-T) – 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_001242581.2(RIN2):c.71C>T(p.Pro24Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,545,556 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P24P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 29)

Exomes 𝑓: 0.0050 ( 41 hom. )

Consequence

RIN2
NM_001242581.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.304

Publications

3 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

RIN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043200552).

BP6

Variant 20-19886740-C-T is Benign according to our data. Variant chr20-19886740-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 444566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00292 (444/151844) while in subpopulation NFE AF = 0.00539 (366/67964). AF 95% confidence interval is 0.00493. There are 1 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242581.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIN2	NM_018993.4	MANE Select	c.-36-2826C>T		intron	N/A	NP_061866.1	Q8WYP3-1
RIN2	NM_001242581.2		c.71C>T	p.Pro24Leu	missense	Exon 1 of 12	NP_001229510.1	Q8WYP3-2
RIN2	NM_001378238.1		c.-581-2826C>T		intron	N/A	NP_001365167.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-2826C>T	intron	N/A	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1		c.-77C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000944197.1		c.-77C>T	5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	ENSP00000614256.1

Frequencies

GnomAD3 genomes

AF:

0.00293

AC:

444

AN:

151728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000872

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00124

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00538

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00242

AC:

355

AN:

146716

AF XY:

0.00233

show subpopulations

Gnomad AFR exome

AF:

0.000427

Gnomad AMR exome

AF:

0.000593

Gnomad ASJ exome

AF:

0.000121

Gnomad EAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00177

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00185

GnomAD4 exome

AF:

0.00503

AC:

7015

AN:

1393712

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

3378

AN XY:

687434

show subpopulations

African (AFR)

AF:

0.000803

AC:

AN:

31146

American (AMR)

AF:

0.000755

AC:

AN:

34450

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

25008

East Asian (EAS)

AF:

0.000532

AC:

AN:

35722

South Asian (SAS)

AF:

0.000167

AC:

AN:

78050

European-Finnish (FIN)

AF:

0.00194

AC:

AN:

48374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00616

AC:

6640

AN:

1077322

Other (OTH)

AF:

0.00340

AC:

197

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

296

593

889

1186

1482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

268

536

804

1072

1340

<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:

0.00292

AC:

444

AN:

151844

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

200

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.000869

AC:

AN:

41426

American (AMR)

AF:

0.00138

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000776

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

10506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00539

AC:

366

AN:

67964

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

103

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:

0.00358

Hom.:

Bravo

AF:

0.00294

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00415

AC:

ExAC

AF:

0.00118

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

RIN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.4

(source)

DANN

Benign

0.85

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.45

M_CAP

Benign

0.021

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

PhyloP100

-0.30

PrimateAI

Benign

0.23

PROVEAN

Benign

0.13

REVEL

Benign

0.0080

Sift

Pathogenic

0.0

Vest4

0.076

MVP

0.17

MPC

0.20

ClinPred

0.028

GERP RS

-7.0

PromoterAI

-0.19

Neutral

(source)

gMVP

0.036

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over