Genetic Variant NM_018993.4:c.84C>T (chr20-19935125-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_018993.4(RIN2):c.84C>T(p.Ile28Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,602,132 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 8 hom., cov: 31)

Exomes 𝑓: 0.0091 ( 92 hom. )

Consequence

RIN2
NM_018993.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.784

Publications

9 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 20-19935125-C-T is Benign according to our data. Variant chr20-19935125-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.784 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00647 (985/152206) while in subpopulation NFE AF = 0.0092 (626/68014). AF 95% confidence interval is 0.00861. There are 8 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

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
RIN2	NM_018993.4	MANE Select	c.84C>T	p.Ile28Ile	synonymous	Exon 4 of 13	NP_061866.1
RIN2	NM_001378238.1		c.-462C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	NP_001365167.1
RIN2	NM_001242581.2		c.231C>T	p.Ile77Ile	synonymous	Exon 3 of 12	NP_001229510.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RIN2	ENST00000255006.12	TSL:2 MANE Select	c.84C>T	p.Ile28Ile	synonymous	Exon 4 of 13	ENSP00000255006.7
RIN2	ENST00000440354.2	TSL:1	c.84C>T	p.Ile28Ile	synonymous	Exon 2 of 8	ENSP00000391239.2
RIN2	ENST00000484638.1	TSL:1	n.1C>T		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes

AF:

0.00648

AC:

985

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.0231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00689

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00920

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00669

AC:

1549

AN:

231368

AF XY:

0.00667

show subpopulations

Gnomad AFR exome

AF:

0.00144

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00603

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.00977

GnomAD4 exome

AF:

0.00911

AC:

13203

AN:

1449926

Hom.:

Cov.:

AF XY:

0.00904

AC XY:

6506

AN XY:

719944

show subpopulations

African (AFR)

AF:

0.00138

AC:

AN:

33246

American (AMR)

AF:

0.00313

AC:

135

AN:

43066

Ashkenazi Jewish (ASJ)

AF:

0.0162

AC:

419

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39174

South Asian (SAS)

AF:

0.00189

AC:

158

AN:

83756

European-Finnish (FIN)

AF:

0.00661

AC:

348

AN:

52676

Middle Eastern (MID)

AF:

0.00747

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0104

AC:

11488

AN:

1106324

Other (OTH)

AF:

0.00943

AC:

566

AN:

60018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

608

1216

1825

2433

3041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.00647

AC:

985

AN:

152206

Hom.:

Cov.:

AF XY:

0.00625

AC XY:

465

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

41528

American (AMR)

AF:

0.00655

AC:

100

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00145

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00689

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00920

AC:

626

AN:

68014

Other (OTH)

AF:

0.00805

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00833

Hom.:

Bravo

AF:

0.00650

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

RIN2 syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=99/1

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over