Genetic Variant RIN2:c.-36-2825G>C (chr20-19886741-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_018993.4(RIN2):c.-36-2825G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,545,992 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 29)

Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

RIN2
NM_018993.4 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.964

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: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 20-19886741-G-C is Benign according to our data. Variant chr20-19886741-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2056418.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4 link	c.-36-2825G>C		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.-36-2825G>C	intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7	Q8WYP3-1
RIN2	ENST00000648440.1 link	c.-76G>C	5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1	Q8WYP3-1
RIN2	ENST00000432334.2 link	n.537-2825G>C	intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1 link	n.618-2825G>C	intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000974

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

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

GnomAD2 exomes

AF:

0.0000138

AC:

AN:

144448

AF XY:

0.0000129

show subpopulations

Gnomad AFR exome

AF:

0.000144

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000236

GnomAD4 exome

AF:

0.0000122

AC:

AN:

1394646

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

687948

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

31172

American (AMR)

AF:

0.00

AC:

AN:

34764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25054

East Asian (EAS)

AF:

0.0000560

AC:

AN:

35710

South Asian (SAS)

AF:

0.00

AC:

AN:

78252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077620

Other (OTH)

AF:

0.000207

AC:

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000463

AC:

AN:

151346

Hom.:

Cov.:

AF XY:

0.0000676

AC XY:

AN XY:

73934

show subpopulations

African (AFR)

AF:

0.000146

AC:

AN:

41206

American (AMR)

AF:

0.00

AC:

AN:

15140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000195

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

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

-0.84

CADD

Benign

0.17

(source)

DANN

Benign

0.65

PhyloP100

-0.96

PromoterAI

-0.17

Neutral

(source)

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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20-19886741-G-C

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