Genetic Variant NM_018993.4:c.-36-2954_-36-2952delCTT (chr20-19886593-CCTT-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.-36-2954_-36-2952delCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 786,188 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 0.00010 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.157

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.-36-2954_-36-2952delCTT		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.-36-2954_-36-2952delCTT	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1 link	c.-205_-203delCTT	5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-2954_537-2952delCTT	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-2954_618-2952delCTT	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000949

AC:

AN:

147514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000743

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000174

AC:

111

AN:

638602

Hom.:

AF XY:

0.000166

AC XY:

AN XY:

336662

show subpopulations

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

African (AFR)

AF:

0.0000702

AC:

AN:

14254

American (AMR)

AF:

0.000331

AC:

AN:

24202

Ashkenazi Jewish (ASJ)

AF:

0.000274

AC:

AN:

18266

East Asian (EAS)

AF:

0.0000317

AC:

AN:

31518

South Asian (SAS)

AF:

0.000319

AC:

AN:

53356

European-Finnish (FIN)

AF:

0.000232

AC:

AN:

43158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3654

European-Non Finnish (NFE)

AF:

0.000146

AC:

AN:

418190

Other (OTH)

AF:

0.000250

AC:

AN:

32004

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.272

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000102

AC:

AN:

147586

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

71788

show subpopulations

African (AFR)

AF:

0.000177

AC:

AN:

39600

American (AMR)

AF:

0.000137

AC:

AN:

14572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.000199

AC:

AN:

5028

South Asian (SAS)

AF:

0.00

AC:

AN:

4608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000743

AC:

AN:

67262

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.404

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

-0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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NM_018993.4:c.-36-2954_-36-2952delCTT

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