20-19886612-CTTTTTTTTTTT-CTTT

Variant names:

• chr20-19886612-CTTTTTTTT-C
• rs11362637
• NM_018993.4:c.-36-2942_-36-2935delTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018993.4(RIN2):​c.-36-2942_-36-2935delTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 520,924 control chromosomes in the GnomAD database, including 27 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (19 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.204
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 20-19886612-CTTTTTTTT-C is Benign according to our data. Variant chr20-19886612-CTTTTTTTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1191188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00914 (1054/115272) while in subpopulation AFR AF = 0.0343 (1009/29430). AF 95% confidence interval is 0.0325. There are 19 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2942_-36-2935delTTTTTTTT		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.-36-2942_-36-2935delTTTTTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-193_-186delTTTTTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2942_537-2935delTTTTTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2942_618-2935delTTTTTTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1046 AN: 115284 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000332

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000873

Gnomad OTH AF: 0.00587

GnomAD4 exome AF: 0.00121 AC: 490 AN: 405652 Hom.: 8 AF XY: 0.00101 AC XY: 221 AN XY: 219186

African (AFR) AF: 0.0431 AC: 368 AN: 8542

American (AMR) AF: 0.00196 AC: 32 AN: 16342

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 24372

South Asian (SAS) AF: 0.000198 AC: 8 AN: 40320

European-Finnish (FIN) AF: 0.0000305 AC: 1 AN: 32820

Middle Eastern (MID) AF: 0.00129 AC: 3 AN: 2328

European-Non Finnish (NFE) AF: 0.0000974 AC: 24 AN: 246484

Other (OTH) AF: 0.00251 AC: 54 AN: 21488

GnomAD4 genome AF: 0.00914 AC: 1054 AN: 115272 Hom.: 19 Cov.: 0 AF XY: 0.00891 AC XY: 483 AN XY: 54210

African (AFR) AF: 0.0343 AC: 1009 AN: 29430

American (AMR) AF: 0.00275 AC: 30 AN: 10900

Ashkenazi Jewish (ASJ) AF: 0.000332 AC: 1 AN: 3012

East Asian (EAS) AF: 0.00 AC: 0 AN: 4058

South Asian (SAS) AF: 0.00 AC: 0 AN: 3390

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000873 AC: 5 AN: 57262

Other (OTH) AF: 0.00584 AC: 9 AN: 1540

Alfa AF: 0.00 Hom.: 309

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
Mutation Taster		=300/0	polymorphism

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;