rs181853315

Positions:

• chr20-19935125-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_018993.4(RIN2):​c.84C>T​(p.Ile28=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.784

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIN2	NM_018993.4	c.84C>T	p.Ile28=	synonymous_variant	4/13	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.84C>T	p.Ile28=	synonymous_variant	4/13	2	NM_018993.4	ENSP00000255006	P1

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 985 AN: 152088 Hom.: 8 Cov.: 31

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

GnomAD3 exomes AF: 0.00669 AC: 1549 AN: 231368 Hom.: 11 AF XY: 0.00667 AC XY: 833 AN XY: 124876

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 SAS exome AF: 0.00204

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.: 92 Cov.: 30 AF XY: 0.00904 AC XY: 6506 AN XY: 719944

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.0162

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00661

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.00943

GnomAD4 genome AF: 0.00647 AC: 985 AN: 152206 Hom.: 8 Cov.: 31 AF XY: 0.00625 AC XY: 465 AN XY: 74412

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00655

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00689

Gnomad4 NFE AF: 0.00920

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00833 Hom.: 0

Bravo AF: 0.00650

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RIN2: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 24, 2015

- -

RIN2 syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

LitVar

Other links and lift over

dbSNP: rs181853315; hg19: chr20-19915769; COSMIC: COSV99658025;