Genetic Variant NM_018993.4:c.-36-2946_-36-2935dupTTTTTTTTTTTT (chr20-19886612-C-CTTTTTTTTTTTT) – 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.-36-2946_-36-2935dupTTTTTTTTTTTT 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 0.000026 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00011 ( 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, 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.-36-2946_-36-2935dupTTTTTTTTTTTT		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.-36-2946_-36-2935dupTTTTTTTTTTTT	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1 link	c.-197_-186dupTTTTTTTTTTTT	5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-2946_537-2935dupTTTTTTTTTTTT	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-2946_618-2935dupTTTTTTTTTTTT	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000260

AC:

AN:

115272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000340

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:

0.0000349

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

AN:

405678

Hom.:

Cov.:

AF XY:

0.0000958

AC XY:

AN XY:

219196

show subpopulations

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

African (AFR)

AF:

0.000234

AC:

AN:

8542

American (AMR)

AF:

0.000245

AC:

AN:

16342

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

12956

East Asian (EAS)

AF:

0.000164

AC:

AN:

24372

South Asian (SAS)

AF:

0.000223

AC:

AN:

40322

European-Finnish (FIN)

AF:

0.0000305

AC:

AN:

32824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2328

European-Non Finnish (NFE)

AF:

0.0000811

AC:

AN:

246502

Other (OTH)

AF:

0.0000931

AC:

AN:

21490

⚠️ 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: 0.369

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:

0.0000260

AC:

AN:

115272

Hom.:

Cov.:

AF XY:

0.0000369

AC XY:

AN XY:

54190

show subpopulations

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

African (AFR)

AF:

0.0000340

AC:

AN:

29384

American (AMR)

AF:

0.00

AC:

AN:

10896

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:

0.0000349

AC:

AN:

57264

Other (OTH)

AF:

0.00

AC:

AN:

1532

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0160444), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000430

Hom.:

309

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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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