rs72242041

Variant names:

• chr20-19886698-CT-C
• rs72242041
• NM_018993.4:c.-36-2865delT

Your query was ambiguous. Multiple possible variants found:

• chr20-19886698-CT-C
• chr20-19886698-CT-CTT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001242581.2(RIN2):​c.32delT​(p.Leu11TyrfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,539,418 control chromosomes in the GnomAD database, including 200 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (97 hom., cov: 29)
  • Exomes 𝑓: 0.0023 (103 hom.)
• Consequence: RIN2 NM_001242581.2 frameshift
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.244
• Publications: 4 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• BP6: Variant 20-19886698-CT-C is Benign according to our data. Variant chr20-19886698-CT-C is described in ClinVar as Benign. ClinVar VariationId is 445625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

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.-36-2865delT		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001242581.2		c.32delT	p.Leu11TyrfsTer40	frameshift	Exon 1 of 12	NP_001229510.1	Q8WYP3-2
	RIN2	NM_001378238.1		c.-581-2865delT		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.-36-2865delT		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-116delT		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-116delT		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3093 AN: 148220 Hom.: 96 Cov.: 29

Gnomad AFR AF: 0.0722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000385

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00397 AC: 596 AN: 150168 AF XY: 0.00336

Gnomad AFR exome AF: 0.0684

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000377

Gnomad OTH exome AF: 0.00206

GnomAD4 exome AF: 0.00230 AC: 3205 AN: 1391094 Hom.: 103 Cov.: 30 AF XY: 0.00206 AC XY: 1415 AN XY: 686086

African (AFR) AF: 0.0728 AC: 2280 AN: 31332

American (AMR) AF: 0.00448 AC: 159 AN: 35460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24890

East Asian (EAS) AF: 0.00 AC: 0 AN: 35244

South Asian (SAS) AF: 0.000253 AC: 20 AN: 79116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47808

Middle Eastern (MID) AF: 0.00247 AC: 14 AN: 5660

European-Non Finnish (NFE) AF: 0.000414 AC: 445 AN: 1073984

Other (OTH) AF: 0.00498 AC: 287 AN: 57600

GnomAD4 genome AF: 0.0209 AC: 3098 AN: 148324 Hom.: 97 Cov.: 29 AF XY: 0.0198 AC XY: 1427 AN XY: 72064

African (AFR) AF: 0.0721 AC: 2900 AN: 40196

American (AMR) AF: 0.00935 AC: 137 AN: 14652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000385 AC: 26 AN: 67452

Other (OTH) AF: 0.0166 AC: 34 AN: 2050

Alfa AF: 0.00281 Hom.: 2

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24
Mutation Taster		=169/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72242041; hg19: chr20-19867342;