rs3803981

Positions:

• chr20-19970890-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018993.4(RIN2):​c.589T>A​(p.Ser197Thr) variant causes a missense change. The variant allele was found at a frequency of 0.153 in 1,612,492 control chromosomes in the GnomAD database, including 19,608 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S197L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1765 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17843 hom.)
• Consequence: RIN2 NM_018993.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.88

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010179281).
• BP6: Variant 20-19970890-T-A is Benign according to our data. Variant chr20-19970890-T-A is described in ClinVar as [Benign]. Clinvar id is 257655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19970890-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.589T>A	p.Ser197Thr	missense_variant	8/13	ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.589T>A	p.Ser197Thr	missense_variant	8/13	2	NM_018993.4	P1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22859 AN: 152048 Hom.: 1767 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.0754

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.157

GnomAD3 exomes AF: 0.152 AC: 37812 AN: 247982 Hom.: 3152 AF XY: 0.149 AC XY: 19980 AN XY: 134464

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.0820

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.153 AC: 223428 AN: 1460326 Hom.: 17843 Cov.: 31 AF XY: 0.151 AC XY: 109484 AN XY: 726396

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.165

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.0825

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.159

GnomAD4 genome AF: 0.150 AC: 22866 AN: 152166 Hom.: 1765 Cov.: 32 AF XY: 0.150 AC XY: 11163 AN XY: 74398

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.0754

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.147

Gnomad4 OTH AF: 0.156

Alfa AF: 0.154 Hom.: 1425

Bravo AF: 0.158

TwinsUK AF: 0.156 AC: 577

ALSPAC AF: 0.157 AC: 606

ESP6500AA AF: 0.141 AC: 547

ESP6500EA AF: 0.152 AC: 1255

ExAC AF: 0.149 AC: 18017

Asia WGS AF: 0.143 AC: 495 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.21
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.55	T;T
MetaRNN	Benign	0.0010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	0.55	P;P
PrimateAI	Benign	0.43	T
Polyphen		0.0	B;.
Vest4		0.014
MPC		0.17
ClinPred		0.011	T
GERP RS		4.6
Varity_R		0.22
gMVP		0.30

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: rs3803981; hg19: chr20-19951534; COSMIC: COSV54784876;