Genetic Variant RIN2:c.-36-3168C>T (chr20-19886398-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.-36-3168C>T		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.-36-3168C>T	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-3168C>T	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-3168C>T	intron_variant	Intron 3 of 3
RIN2	ENST00000648440.1 link	c.-419C>T	upstream_gene_variant				ENSP00000498085.1	Q8WYP3-1

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

Gnomad4 AFR exome

AF:

0.350

Gnomad4 AMR exome

AF:

0.216

Gnomad4 ASJ exome

AF:

0.257

Gnomad4 EAS exome

AF:

0.267

Gnomad4 SAS exome

AF:

0.225

Gnomad4 FIN exome

AF:

0.212

Gnomad4 NFE exome

AF:

0.187

Gnomad4 OTH exome

AF:

0.215

GnomAD4 genome

AF:

0.247

AC:

37611

AN:

152002

Hom.:

5049

Cov.:

AF XY:

0.248

AC XY:

18450

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.354

Gnomad4 AMR

AF:

0.217

Gnomad4 ASJ

AF:

0.271

Gnomad4 EAS

AF:

0.302

Gnomad4 SAS

AF:

0.248

Gnomad4 FIN

AF:

0.227

Gnomad4 NFE

AF:

0.189

Gnomad4 OTH

AF:

0.236

Alfa

AF:

0.198

Hom.:

4176

Bravo

AF:

0.254

Asia WGS

AF:

0.294

AC:

1025

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.9

DANN

Benign

0.89

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over