rs371219190

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_018993.4(RIN2):c.942C>T(p.Pro314Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

RIN2
NM_018993.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.179

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 20-19974967-C-T is Benign according to our data. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19974967-C-T is described in CliVar as Likely_benign. Clinvar id is 436533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.179 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.942C>T	p.Pro314Pro	synonymous_variant	Exon 9 of 13	ENST00000255006.12	NP_061866.1	Q8WYP3-1A1A4T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIN2	ENST00000255006.12 link	c.942C>T	p.Pro314Pro	synonymous_variant	Exon 9 of 13	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000484638.1 link	n.786C>T		non_coding_transcript_exon_variant	Exon 5 of 9	1
RIN2	ENST00000440354.2 link	c.463+14156C>T		intron_variant	Intron 4 of 7	1		ENSP00000391239.2	E7EPJ1
RIN2	ENST00000648440.1 link	c.942C>T	p.Pro314Pro	synonymous_variant	Exon 8 of 12			ENSP00000498085.1	Q8WYP3-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000687

AC:

AN:

247598

AF XY:

0.0000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1460978

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

726764

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000895

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52916

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000774

AC:

AN:

1111668

Other (OTH)

AF:

0.0000331

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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

AF:

0.0000460

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41400

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

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:

0.0000712

Hom.:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 31, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.8

(source)

DANN

Benign

0.93

PhyloP100

0.18

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over