20-19886667-G-A

Variant names:

• chr20-19886667-G-A
• rs2038209466
• NM_018993.4:c.-36-2899G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001242581.2(RIN2):​c.-3G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RIN2 NM_001242581.2 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.82
• Publications: 0 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-19886667-G-A is Benign according to our data. Variant chr20-19886667-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3049804.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242581.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.-36-2899G>A		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001242581.2		c.-3G>A		5_prime_UTR	Exon 1 of 12	NP_001229510.1	Q8WYP3-2
	RIN2	NM_001378238.1		c.-581-2899G>A		intron	N/A	NP_001365167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-2899G>A		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-150G>A		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-150G>A		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes AF: 0.00000687 AC: 1 AN: 145546 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 13 AN: 1241390 Hom.: 0 Cov.: 20 AF XY: 0.0000129 AC XY: 8 AN XY: 619328

African (AFR) AF: 0.00 AC: 0 AN: 28210

American (AMR) AF: 0.00 AC: 0 AN: 35388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24190

East Asian (EAS) AF: 0.0000860 AC: 3 AN: 34878

South Asian (SAS) AF: 0.00 AC: 0 AN: 75850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5390

European-Non Finnish (NFE) AF: 0.0000107 AC: 10 AN: 936562

Other (OTH) AF: 0.00 AC: 0 AN: 52868

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000687 AC: 1 AN: 145630 Hom.: 0 Cov.: 28 AF XY: 0.0000142 AC XY: 1 AN XY: 70458

African (AFR) AF: 0.00 AC: 0 AN: 38724

American (AMR) AF: 0.00 AC: 0 AN: 14406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4944

South Asian (SAS) AF: 0.00 AC: 0 AN: 4646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67168

Other (OTH) AF: 0.00 AC: 0 AN: 1986

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	RIN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.36
PhyloP100		1.8
PromoterAI		-0.012	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2038209466;

hg19: chr20-19867311;