rs368610064

chr20-19990160-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_018993.4(RIN2):c.1917G>A(p.Leu639=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,603,994 control chromosomes in the GnomAD database, including 12 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 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (12 hom.)
• Consequence: RIN2 NM_018993.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.62

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 20-19990160-G-A is Benign according to our data. Variant chr20-19990160-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 391266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.62 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00229 (349/152350) while in subpopulation NFE AF= 0.00387 (263/68036). AF 95% confidence interval is 0.00348. There are 0 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.1917G>A	p.Leu639=	synonymous_variant	10/13	ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.1917G>A	p.Leu639=	synonymous_variant	10/13	2	NM_018993.4	P1
RIN2	ENST00000440354.2	c.618G>A	p.Leu206=	synonymous_variant	5/8	1
RIN2	ENST00000484638.1	n.1761G>A		non_coding_transcript_exon_variant	6/9	1
RIN2	ENST00000648440.1	c.1917G>A	p.Leu639=	synonymous_variant	9/12			P1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 349 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00214 AC: 491 AN: 228918 Hom.: 1 AF XY: 0.00205 AC XY: 254 AN XY: 123938

Gnomad AFR exome AF: 0.000667

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.000417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000712

Gnomad FIN exome AF: 0.000196

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.00374 AC: 5422 AN: 1451644 Hom.: 12 Cov.: 33 AF XY: 0.00360 AC XY: 2598 AN XY: 721046

Gnomad4 AFR exome AF: 0.000630

Gnomad4 AMR exome AF: 0.00337

Gnomad4 ASJ exome AF: 0.000348

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000237

Gnomad4 FIN exome AF: 0.000265

Gnomad4 NFE exome AF: 0.00448

Gnomad4 OTH exome AF: 0.00427

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74508

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00387

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00291 Hom.: 1

Bravo AF: 0.00260

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 24, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RIN2: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	5.6
Dann	Benign	0.74

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: rs368610064; hg19: chr20-19970804; COSMIC: COSV54790124;