rs2076584

Variant names:

• chr20-19990061-C-T
• rs2076584
• NM_018993.4:c.1818C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_018993.4(RIN2):​c.1818C>T​(p.His606His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,596,974 control chromosomes in the GnomAD database, including 92,739 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10187 hom., cov: 33)
  • Exomes 𝑓: 0.33 (82552 hom.)
• Consequence: RIN2 NM_018993.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.255

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=-0.36).
• BP6: Variant 20-19990061-C-T is Benign according to our data. Variant chr20-19990061-C-T is described in ClinVar as [Benign]. Clinvar id is 257654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-19990061-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.255 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.1818C>T	p.His606His	synonymous_variant	Exon 10 of 13	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.1818C>T	p.His606His	synonymous_variant	Exon 10 of 13	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000440354.2	c.519C>T	p.His173His	synonymous_variant	Exon 5 of 8	1		ENSP00000391239.2
RIN2	ENST00000484638.1	n.1662C>T		non_coding_transcript_exon_variant	Exon 6 of 9	1
RIN2	ENST00000648440.1	c.1818C>T	p.His606His	synonymous_variant	Exon 9 of 12			ENSP00000498085.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53782 AN: 152008 Hom.: 10172 Cov.: 33

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.274

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.368 AC: 82119 AN: 223160 Hom.: 17420 AF XY: 0.353 AC XY: 42580 AN XY: 120504

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.710

Gnomad SAS exome AF: 0.246

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.304

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.325 AC: 469719 AN: 1444848 Hom.: 82552 Cov.: 34 AF XY: 0.322 AC XY: 230974 AN XY: 716884

Gnomad4 AFR exome AF: 0.384

Gnomad4 AMR exome AF: 0.579

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.743

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.242

Gnomad4 NFE exome AF: 0.308

Gnomad4 OTH exome AF: 0.339

GnomAD4 genome AF: 0.354 AC: 53832 AN: 152126 Hom.: 10187 Cov.: 33 AF XY: 0.354 AC XY: 26341 AN XY: 74374

Gnomad4 AFR AF: 0.386

Gnomad4 AMR AF: 0.471

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.712

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.378

Alfa AF: 0.329 Hom.: 18405

Bravo AF: 0.382

Asia WGS AF: 0.466 AC: 1616 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RIN2 syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: 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	-0.36
CADD	Benign	7.0
DANN	Benign	0.47

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: rs2076584; hg19: chr20-19970705; COSMIC: COSV54788376;