Variant 20-19975749-AC-ACC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_018993.4(RIN2):c.1731dup(p.Ile578HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

RIN2
NM_018993.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.0610

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-19975749-A-AC is Pathogenic according to our data. Variant chr20-19975749-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 137627.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4 linkuse as main transcript	c.1731dup	p.Ile578HisfsTer7	frameshift_variant	9/13	ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12 linkuse as main transcript	c.1731dup	p.Ile578HisfsTer7	frameshift_variant	9/13	2	NM_018993.4	P1	Q8WYP3-1
RIN2	ENST00000440354.2 linkuse as main transcript	c.464-14250dup		intron_variant		1
RIN2	ENST00000484638.1 linkuse as main transcript	n.1575dup		non_coding_transcript_exon_variant	5/9	1
RIN2	ENST00000648440.1 linkuse as main transcript	c.1731dup	p.Ile578HisfsTer7	frameshift_variant	8/12			P1	Q8WYP3-1

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1460098

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726262

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000190

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150090

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73144

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000489

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2021

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Ile578Hisfs*7) in the RIN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RIN2 are known to be pathogenic (PMID: 19631308). This premature translational stop signal has been observed in individuals with RIN2-related conditions (PMID: 24449201, 27277385). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 137627). This variant is also known as c.1878_1879insC, c.1878dupC, p.Ile627Hisfs*7. -

RIN2 syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over