20-19886698-CT-CTT

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001242581.2(RIN2):​c.32dupT​(p.Leu11PhefsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: RIN2 NM_001242581.2 frameshift
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 6 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.
• PM2: Very rare variant in population databases, with high coverage

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.-36-2865dupT		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001242581.2		c.32dupT	p.Leu11PhefsTer58	frameshift	Exon 1 of 12	NP_001229510.1	Q8WYP3-2
	RIN2	NM_001378238.1		c.-581-2865dupT		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.-36-2865dupT		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-116dupT		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-116dupT		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.24

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: rs72242041; hg19: chr20-19867342;