Genetic Variant RIN2:c.-36-2935delT (chr20-19886612-CT-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_018993.4(RIN2):c.-36-2935delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.38 ( 7053 hom., cov: 0)

Exomes 𝑓: 0.27 ( 216 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.844

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: Benign. The variant received -10 ACMG points.

BP6

Variant 20-19886612-CT-C is Benign according to our data. Variant chr20-19886612-CT-C is described in ClinVar as [Benign]. Clinvar id is 1257379.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.-36-2935delT		intron_variant	Intron 2 of 12	ENST00000255006.12	NP_061866.1	Q8WYP3-1A1A4T0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIN2	ENST00000255006.12 link	c.-36-2935delT	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1 link	c.-186delT	5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-2935delT	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-2935delT	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

43481

AN:

115110

Hom.:

7054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.294

Gnomad AMI

AF:

0.385

Gnomad AMR

AF:

0.368

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.346

GnomAD4 exome

AF:

0.269

AC:

107749

AN:

400462

Hom.:

216

Cov.:

AF XY:

0.267

AC XY:

57828

AN XY:

216314

show subpopulations

African (AFR)

AF:

0.248

AC:

2065

AN:

8318

American (AMR)

AF:

0.239

AC:

3858

AN:

16152

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

2925

AN:

12810

East Asian (EAS)

AF:

0.297

AC:

7120

AN:

24008

South Asian (SAS)

AF:

0.228

AC:

9045

AN:

39692

European-Finnish (FIN)

AF:

0.231

AC:

7506

AN:

32430

Middle Eastern (MID)

AF:

0.203

AC:

470

AN:

2310

European-Non Finnish (NFE)

AF:

0.282

AC:

68800

AN:

243558

Other (OTH)

AF:

0.281

AC:

5960

AN:

21184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.402

Heterozygous variant carriers

3815

7630

11446

15261

19076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.378

AC:

43474

AN:

115096

Hom.:

7053

Cov.:

AF XY:

0.375

AC XY:

20291

AN XY:

54142

show subpopulations

African (AFR)

AF:

0.294

AC:

8624

AN:

29352

American (AMR)

AF:

0.368

AC:

4004

AN:

10882

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

962

AN:

2998

East Asian (EAS)

AF:

0.372

AC:

1509

AN:

4058

South Asian (SAS)

AF:

0.405

AC:

1371

AN:

3388

European-Finnish (FIN)

AF:

0.421

AC:

1969

AN:

4680

Middle Eastern (MID)

AF:

0.233

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.422

AC:

24145

AN:

57190

Other (OTH)

AF:

0.347

AC:

535

AN:

1544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1131

2262

3394

4525

5656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.196

Hom.:

309

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 16, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.84

Mutation Taster

=299/1

polymorphism (auto)

(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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20-19886612-CT-C

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