20-19975363-G-C

Position:

• chr20-19975363-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018993.4(RIN2):​c.1338G>C​(p.Arg446=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,852 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (14 hom.)
• Consequence: RIN2 NM_018993.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.09

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-19975363-G-C is Benign according to our data. Variant chr20-19975363-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 389384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00234 (357/152388) while in subpopulation AMR AF= 0.00235 (36/15310). AF 95% confidence interval is 0.002. There are 1 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIN2	NM_018993.4	c.1338G>C	p.Arg446=	synonymous_variant	9/13	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.1338G>C	p.Arg446=	synonymous_variant	9/13	2	NM_018993.4	ENSP00000255006	P1
RIN2	ENST00000440354.2	c.463+14552G>C		intron_variant		1		ENSP00000391239
RIN2	ENST00000484638.1	n.1182G>C		non_coding_transcript_exon_variant	5/9	1
RIN2	ENST00000648440.1	c.1338G>C	p.Arg446=	synonymous_variant	8/12			ENSP00000498085	P1

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 357 AN: 152270 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00254 AC: 629 AN: 248038 Hom.: 4 AF XY: 0.00264 AC XY: 356 AN XY: 134704

Gnomad AFR exome AF: 0.000392

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00865

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00381

GnomAD4 exome AF: 0.00241 AC: 3525 AN: 1461464 Hom.: 14 Cov.: 36 AF XY: 0.00241 AC XY: 1755 AN XY: 726994

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00372

Gnomad4 FIN exome AF: 0.00823

Gnomad4 NFE exome AF: 0.00228

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152388 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74518

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.00157

EpiCase AF: 0.00294

EpiControl AF: 0.00321

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RIN2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 26, 2015

- -

RIN2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 20, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.85

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: rs367993633; hg19: chr20-19956007; COSMIC: COSV99656824; COSMIC: COSV99656824;