Genetic Variant RIN2:c.-36-2937_-36-2935dupTTT (chr20-19886612-C-CTTT) – 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.-36-2937_-36-2935dupTTT 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 0.00069 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0016 ( 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.-36-2937_-36-2935dupTTT		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.-36-2937_-36-2935dupTTT	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1 link	c.-188_-186dupTTT	5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-2937_537-2935dupTTT	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-2937_618-2935dupTTT	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.000686

AC:

AN:

115176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000443

Gnomad AMI

AF:

0.00126

Gnomad AMR

AF:

0.000275

Gnomad ASJ

AF:

0.00200

Gnomad EAS

AF:

0.000245

Gnomad SAS

AF:

0.000586

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000927

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00161

AC:

654

AN:

405432

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

368

AN XY:

219068

show subpopulations

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

African (AFR)

AF:

0.00223

AC:

AN:

8528

American (AMR)

AF:

0.00324

AC:

AN:

16334

Ashkenazi Jewish (ASJ)

AF:

0.00139

AC:

AN:

12956

East Asian (EAS)

AF:

0.00156

AC:

AN:

24356

South Asian (SAS)

AF:

0.00355

AC:

143

AN:

40274

European-Finnish (FIN)

AF:

0.000579

AC:

AN:

32806

Middle Eastern (MID)

AF:

0.000430

AC:

AN:

2328

European-Non Finnish (NFE)

AF:

0.00132

AC:

326

AN:

246376

Other (OTH)

AF:

0.00172

AC:

AN:

21474

⚠️ 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: 0.358

Heterozygous variant carriers

116

155

194

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:

0.000686

AC:

AN:

115164

Hom.:

Cov.:

AF XY:

0.000812

AC XY:

AN XY:

54154

show subpopulations

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

African (AFR)

AF:

0.000442

AC:

AN:

29402

American (AMR)

AF:

0.000275

AC:

AN:

10896

Ashkenazi Jewish (ASJ)

AF:

0.00200

AC:

AN:

3004

East Asian (EAS)

AF:

0.000246

AC:

AN:

4058

South Asian (SAS)

AF:

0.000590

AC:

AN:

3390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.000927

AC:

AN:

57196

Other (OTH)

AF:

0.00

AC:

AN:

1538

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.303

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

Alfa

AF:

0.00

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over