Genetic Variant RIN2:c.-36-3168C>T (chr20-19886398-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_StrongBA1

The NM_018993.4(RIN2):c.-36-3168C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 328,602 control chromosomes in the GnomAD database, including 9,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 5049 hom., cov: 31)

Exomes 𝑓: 0.21 ( 4051 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.905

Publications

6 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 (BayesDel_noAF=-0.68).

BP6

Variant 20-19886398-C-T is Benign according to our data. Variant chr20-19886398-C-T is described in ClinVar as Benign. ClinVar VariationId is 683996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
RIN2	NM_018993.4	MANE Select	c.-36-3168C>T	intron	N/A	NP_061866.1	Q8WYP3-1
RIN2	NM_001378238.1		c.-581-3168C>T	intron	N/A	NP_001365167.1
RIN2	NM_001242581.2		c.-272C>T	upstream_gene	N/A	NP_001229510.1	Q8WYP3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-3168C>T	intron	N/A	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000944194.1		c.-36-3168C>T	intron	N/A	ENSP00000614253.1
RIN2	ENST00000891327.1		c.-36-3168C>T	intron	N/A	ENSP00000561386.1

Frequencies

GnomAD3 genomes

AF:

0.247

AC:

37569

AN:

151884

Hom.:

5040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.217

Gnomad ASJ

AF:

0.271

Gnomad EAS

AF:

0.303

Gnomad SAS

AF:

0.247

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.228

GnomAD4 exome

AF:

0.207

AC:

36560

AN:

176600

Hom.:

4051

AF XY:

0.207

AC XY:

18693

AN XY:

90204

show subpopulations

African (AFR)

AF:

0.350

AC:

1895

AN:

5412

American (AMR)

AF:

0.216

AC:

1215

AN:

5634

Ashkenazi Jewish (ASJ)

AF:

0.257

AC:

1699

AN:

6620

East Asian (EAS)

AF:

0.267

AC:

4063

AN:

15208

South Asian (SAS)

AF:

0.225

AC:

1054

AN:

4680

European-Finnish (FIN)

AF:

0.212

AC:

2507

AN:

11838

Middle Eastern (MID)

AF:

0.239

AC:

221

AN:

924

European-Non Finnish (NFE)

AF:

0.187

AC:

21372

AN:

114502

Other (OTH)

AF:

0.215

AC:

2534

AN:

11782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1410

2821

4231

5642

7052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.247

AC:

37611

AN:

152002

Hom.:

5049

Cov.:

AF XY:

0.248

AC XY:

18450

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.354

AC:

14673

AN:

41452

American (AMR)

AF:

0.217

AC:

3315

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

938

AN:

3462

East Asian (EAS)

AF:

0.302

AC:

1557

AN:

5152

South Asian (SAS)

AF:

0.248

AC:

1191

AN:

4806

European-Finnish (FIN)

AF:

0.227

AC:

2396

AN:

10556

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.189

AC:

12847

AN:

67980

Other (OTH)

AF:

0.236

AC:

497

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1451

2902

4352

5803

7254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.204

Hom.:

5675

Bravo

AF:

0.254

Asia WGS

AF:

0.294

AC:

1025

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.9

(source)

DANN

Benign

0.89

PhyloP100

-0.91

PromoterAI

-0.22

Neutral

(source)

Splicing

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