20-19886612-CTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTT

Variant names:

• chr20-19886612-C-CTTTTTTTTTTTTTT
• rs11362637
• NM_018993.4:c.-36-2948_-36-2935dupTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018993.4(RIN2):​c.-36-2948_-36-2935dupTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.844
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.-36-2948_-36-2935dupTTTTTTTTTTTTTT		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001378238.1		c.-581-2948_-581-2935dupTTTTTTTTTTTTTT		intron	N/A	NP_001365167.1
	RIN2	NM_001242581.2		c.-58_-57insTTTTTTTTTTTTTT		upstream_gene	N/A	NP_001229510.1	Q8WYP3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-2948_-36-2935dupTTTTTTTTTTTTTT		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-199_-186dupTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-199_-186dupTTTTTTTTTTTTTT		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes AF: 0.0000347 AC: 4 AN: 115280 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000349

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000641 AC: 26 AN: 405692 Hom.: 0 Cov.: 0 AF XY: 0.0000593 AC XY: 13 AN XY: 219206

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000117 AC: 1 AN: 8542

American (AMR) AF: 0.000306 AC: 5 AN: 16344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12956

East Asian (EAS) AF: 0.0000821 AC: 2 AN: 24372

South Asian (SAS) AF: 0.00 AC: 0 AN: 40324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2328

European-Non Finnish (NFE) AF: 0.0000730 AC: 18 AN: 246512

Other (OTH) AF: 0.00 AC: 0 AN: 21490

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000361802), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000347 AC: 4 AN: 115280 Hom.: 0 Cov.: 0 AF XY: 0.0000369 AC XY: 2 AN XY: 54194

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000340 AC: 1 AN: 29384

American (AMR) AF: 0.0000917 AC: 1 AN: 10900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3012

East Asian (EAS) AF: 0.00 AC: 0 AN: 4074

South Asian (SAS) AF: 0.00 AC: 0 AN: 3414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.0000349 AC: 2 AN: 57268

Other (OTH) AF: 0.00 AC: 0 AN: 1532

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11362637; hg19: chr20-19867256;