chr20-19990061-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.1818C>T	p.His606His	synonymous	Exon 10 of 13	NP_061866.1
	RIN2	NM_001242581.2		c.1965C>T	p.His655His	synonymous	Exon 9 of 12	NP_001229510.1
	RIN2	NM_001378238.1		c.1200C>T	p.His400His	synonymous	Exon 9 of 12	NP_001365167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.1818C>T	p.His606His	synonymous	Exon 10 of 13	ENSP00000255006.7
	RIN2	ENST00000440354.2	TSL:1	c.519C>T	p.His173His	synonymous	Exon 5 of 8	ENSP00000391239.2
	RIN2	ENST00000484638.1	TSL:1	n.1662C>T		non_coding_transcript_exon	Exon 6 of 9

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

GnomAD2 exomes AF: 0.368 AC: 82119 AN: 223160 AF XY: 0.353

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 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

African (AFR) AF: 0.384 AC: 12725 AN: 33174

American (AMR) AF: 0.579 AC: 24242 AN: 41868

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8803 AN: 25770

East Asian (EAS) AF: 0.743 AC: 29038 AN: 39088

South Asian (SAS) AF: 0.247 AC: 20633 AN: 83584

European-Finnish (FIN) AF: 0.242 AC: 12746 AN: 52576

Middle Eastern (MID) AF: 0.258 AC: 1485 AN: 5752

European-Non Finnish (NFE) AF: 0.308 AC: 339735 AN: 1103186

Other (OTH) AF: 0.339 AC: 20312 AN: 59850

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

African (AFR) AF: 0.386 AC: 16032 AN: 41482

American (AMR) AF: 0.471 AC: 7213 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1147 AN: 3472

East Asian (EAS) AF: 0.712 AC: 3681 AN: 5170

South Asian (SAS) AF: 0.254 AC: 1226 AN: 4828

European-Finnish (FIN) AF: 0.231 AC: 2442 AN: 10576

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.308 AC: 20954 AN: 67986

Other (OTH) AF: 0.378 AC: 799 AN: 2112

Alfa AF: 0.335 Hom.: 37619

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

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.0
DANN	Benign	0.47
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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