20-19886612-CTTTTTTTTTTT-CTTTTTTTT

Variant names:

• chr20-19886612-CTTT-C
• rs11362637
• NM_018993.4:c.-36-2937_-36-2935delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018993.4(RIN2):​c.-36-2937_-36-2935delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 510,432 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000052 (0 hom., cov: 0)
  • Exomes 𝑓: 0.031 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400
• 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, Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.0336) population. However there is too low homozygotes in high coverage region: (expected more than 74, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2937_-36-2935delTTT		intron_variant	Intron 2 of 12	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2937_-36-2935delTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-188_-186delTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2937_537-2935delTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2937_618-2935delTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000521 AC: 6 AN: 115268 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000245

Gnomad SAS AF: 0.000293

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000175

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0313 AC: 12362 AN: 395164 Hom.: 0 AF XY: 0.0309 AC XY: 6583 AN XY: 213356

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

African (AFR) AF: 0.0274 AC: 229 AN: 8356

American (AMR) AF: 0.0331 AC: 527 AN: 15900

Ashkenazi Jewish (ASJ) AF: 0.0267 AC: 338 AN: 12644

East Asian (EAS) AF: 0.0307 AC: 725 AN: 23614

South Asian (SAS) AF: 0.0229 AC: 905 AN: 39520

European-Finnish (FIN) AF: 0.0228 AC: 731 AN: 32088

Middle Eastern (MID) AF: 0.0237 AC: 54 AN: 2276

European-Non Finnish (NFE) AF: 0.0342 AC: 8208 AN: 239874

Other (OTH) AF: 0.0309 AC: 645 AN: 20892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000521 AC: 6 AN: 115268 Hom.: 0 Cov.: 0 AF XY: 0.0000738 AC XY: 4 AN XY: 54186

African (AFR) AF: 0.000102 AC: 3 AN: 29384

American (AMR) AF: 0.00 AC: 0 AN: 10898

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

East Asian (EAS) AF: 0.000245 AC: 1 AN: 4074

South Asian (SAS) AF: 0.000293 AC: 1 AN: 3414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4672

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

European-Non Finnish (NFE) AF: 0.0000175 AC: 1 AN: 57262

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

Alfa AF: 0.00 Hom.: 309

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.040
Mutation Taster		=300/0	polymorphism

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: rs11362637; hg19: chr20-19867256;