Genetic Variant RIN2:c.-36-2950_-36-2935dupTTTTTTTTTTTTTTTT (chr20-19886612-C-CTTTTTTTTTTTTTTTT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018993.4(RIN2):c.-36-2950_-36-2935dupTTTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RIN2
NM_018993.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.844

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.-36-2950_-36-2935dupTTTTTTTTTTTTTTTT		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.-36-2950_-36-2935dupTTTTTTTTTTTTTTTT	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1 link	c.-201_-186dupTTTTTTTTTTTTTTTT	5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-2950_537-2935dupTTTTTTTTTTTTTTTT	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-2950_618-2935dupTTTTTTTTTTTTTTTT	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

115274

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000296

AC:

AN:

405686

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

219200

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000117

AC:

AN:

8542

American (AMR)

AF:

0.0000612

AC:

AN:

16342

Ashkenazi Jewish (ASJ)

AF:

0.0000772

AC:

AN:

12956

East Asian (EAS)

AF:

0.00

AC:

AN:

24372

South Asian (SAS)

AF:

0.0000496

AC:

AN:

40324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2328

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

246508

Other (OTH)

AF:

0.0000465

AC:

AN:

21490

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000030), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

115274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

54192

African (AFR)

AF:

0.00

AC:

AN:

29384

American (AMR)

AF:

0.00

AC:

AN:

10898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3012

East Asian (EAS)

AF:

0.00

AC:

AN:

4074

South Asian (SAS)

AF:

0.00

AC:

AN:

3414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57264

Other (OTH)

AF:

0.00

AC:

AN:

1532

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.84

Splicing

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

Publications

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chr20-19886612-C-CTTTTTTTTTTTTTTTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over