Genetic Variant RIN2:c.-36-2942_-36-2935dupTTTTTTTT (chr20-19886612-C-CTTTTTTTT) – 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.-36-2942_-36-2935dupTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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

RIN2 links:

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ACMG classification

Classification was made for transcript

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

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.-36-2942_-36-2935dupTTTTTTTT	intron	N/A	NP_061866.1	Q8WYP3-1
RIN2	NM_001378238.1		c.-581-2942_-581-2935dupTTTTTTTT	intron	N/A	NP_001365167.1
RIN2	NM_001242581.2		c.-58_-57insTTTTTTTT	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.-36-2942_-36-2935dupTTTTTTTT	intron	N/A	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1		c.-193_-186dupTTTTTTTT	5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000944201.1		c.-193_-186dupTTTTTTTT	5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes

AF:

0.0000174

AC:

AN:

115262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000918

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:

0.0000175

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000239

AC:

AN:

405658

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

AN XY:

219184

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:

8538

American (AMR)

AF:

0.00110

AC:

AN:

16342

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

12956

East Asian (EAS)

AF:

0.000246

AC:

AN:

24372

South Asian (SAS)

AF:

0.000571

AC:

AN:

40314

European-Finnish (FIN)

AF:

0.000152

AC:

AN:

32824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2328

European-Non Finnish (NFE)

AF:

0.000170

AC:

AN:

246498

Other (OTH)

AF:

0.00

AC:

AN:

21486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000174

AC:

AN:

115262

Hom.:

Cov.:

AF XY:

0.0000185

AC XY:

AN XY:

54186

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29382

American (AMR)

AF:

0.0000918

AC:

AN:

10898

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3012

East Asian (EAS)

AF:

0.00

AC:

AN:

4072

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:

0.0000175

AC:

AN:

57256

Other (OTH)

AF:

0.00

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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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20-19886612-CTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTT

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