Genetic Variant NM_018993.4:c.-36-2826C>A (chr20-19886740-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018993.4(RIN2):c.-36-2826C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,393,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.304

Publications

3 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
RIN2	NM_018993.4	MANE Select	c.-36-2826C>A		intron	N/A	NP_061866.1	Q8WYP3-1
RIN2	NM_001242581.2		c.71C>A	p.Pro24Gln	missense	Exon 1 of 12	NP_001229510.1	Q8WYP3-2
RIN2	NM_001378238.1		c.-581-2826C>A		intron	N/A	NP_001365167.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-2826C>A	intron	N/A	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1		c.-77C>A	5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000944197.1		c.-77C>A	5_prime_UTR	Exon 3 of 14	ENSP00000614256.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

146716

AF XY:

0.0000255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1393808

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

687478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31146

American (AMR)

AF:

0.00

AC:

AN:

34450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25008

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35722

South Asian (SAS)

AF:

0.00

AC:

AN:

78050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077418

Other (OTH)

AF:

0.00

AC:

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.13

(source)

DANN

Benign

0.93

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.33

M_CAP

Benign

0.018

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

-0.30

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.14

REVEL

Benign

0.013

Sift

Pathogenic

0.0

Vest4

0.31

MutPred

0.21

Gain of solvent accessibility (P = 0.0365)

MVP

0.13

MPC

0.17

ClinPred

0.53

GERP RS

-7.0

PromoterAI

0.00040

Neutral

(source)

gMVP

0.050

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.72

Position offset: 1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over