Genetic Variant RIN2:c.-36-2957_-36-2952delCTTCTT (chr20-19886593-CCTTCTT-C) – 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.-36-2957_-36-2952delCTTCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 786,420 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.428

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.-36-2957_-36-2952delCTTCTT		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.-36-2957_-36-2952delCTTCTT	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1 link	c.-208_-203delCTTCTT	5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-2957_537-2952delCTTCTT	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-2957_618-2952delCTTCTT	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

147502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000759

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000687

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:

0.0000673

AC:

AN:

638846

Hom.:

AF XY:

0.0000980

AC XY:

AN XY:

336812

show subpopulations

African (AFR)

AF:

0.000632

AC:

AN:

14244

American (AMR)

AF:

0.0000826

AC:

AN:

24208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18284

East Asian (EAS)

AF:

0.00

AC:

AN:

31518

South Asian (SAS)

AF:

0.000431

AC:

AN:

53414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43210

Middle Eastern (MID)

AF:

0.000274

AC:

AN:

3656

European-Non Finnish (NFE)

AF:

0.00000478

AC:

AN:

418302

Other (OTH)

AF:

0.000187

AC:

AN:

32010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000217

AC:

AN:

147574

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

AN XY:

71782

show subpopulations

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

African (AFR)

AF:

0.000783

AC:

AN:

39586

American (AMR)

AF:

0.0000686

AC:

AN:

14570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5028

South Asian (SAS)

AF:

0.00

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67264

Other (OTH)

AF:

0.00

AC:

AN:

2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.378

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.43

Splicing

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

Publications

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chr20-19886593-CCTTCTT-C

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