NM_018993.4:c.-36-2936_-36-2935dupTT

Variant names:

• chr20-19886612-C-CTT
• rs11362637
• NM_018993.4:c.-36-2936_-36-2935dupTT

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.-36-2936_-36-2935dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 0)
  • Exomes 𝑓: 0.0061 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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, 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-C-CTT is Benign according to our data. Variant chr20-19886612-C-CTT is described in ClinVar as [Likely_benign]. Clinvar id is 1185800.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1236/115156) while in subpopulation AFR AF = 0.0216 (636/29406). AF 95% confidence interval is 0.0202. There are 19 homozygotes in GnomAd4. There are 552 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.-36-2936_-36-2935dupTT		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.-36-2936_-36-2935dupTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-187_-186dupTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2936_537-2935dupTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2936_618-2935dupTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1236 AN: 115168 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00450

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00467

Gnomad SAS AF: 0.00733

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00829

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.00610 AC: 2468 AN: 404514 Hom.: 0 Cov.: 0 AF XY: 0.00619 AC XY: 1353 AN XY: 218592

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

African (AFR) AF: 0.0123 AC: 104 AN: 8478

American (AMR) AF: 0.00811 AC: 132 AN: 16268

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 48 AN: 12922

East Asian (EAS) AF: 0.00762 AC: 185 AN: 24270

South Asian (SAS) AF: 0.00832 AC: 335 AN: 40244

European-Finnish (FIN) AF: 0.00375 AC: 123 AN: 32762

Middle Eastern (MID) AF: 0.00388 AC: 9 AN: 2320

European-Non Finnish (NFE) AF: 0.00572 AC: 1406 AN: 245822

Other (OTH) AF: 0.00588 AC: 126 AN: 21428

⚠️ 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: 0.0107 AC: 1236 AN: 115156 Hom.: 19 Cov.: 0 AF XY: 0.0102 AC XY: 552 AN XY: 54154

African (AFR) AF: 0.0216 AC: 636 AN: 29406

American (AMR) AF: 0.00450 AC: 49 AN: 10890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3006

East Asian (EAS) AF: 0.00469 AC: 19 AN: 4054

South Asian (SAS) AF: 0.00738 AC: 25 AN: 3388

European-Finnish (FIN) AF: 0.00235 AC: 11 AN: 4674

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

European-Non Finnish (NFE) AF: 0.00829 AC: 474 AN: 57196

Other (OTH) AF: 0.0143 AC: 22 AN: 1540

Alfa AF: 0.00287 Hom.: 309

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 23, 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		-0.84
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;