chr20-19886608-TC-T

Variant names:

• chr20-19886608-TC-T
• rs11476169
• NM_018993.4:c.-36-2957delC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_018993.4(RIN2):​c.-36-2957delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 860,530 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (28 hom., cov: 30)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.86
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 20-19886608-TC-T is Benign according to our data. Variant chr20-19886608-TC-T is described in ClinVar as [Benign]. Clinvar id is 1278212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2957delC		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.-36-2957delC		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-208delC		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2957delC		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2957delC		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 1785 AN: 125588 Hom.: 28 Cov.: 30

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000270

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000224

Gnomad OTH AF: 0.0112

GnomAD4 exome AF: 0.000235 AC: 173 AN: 734896 Hom.: 1 Cov.: 10 AF XY: 0.000211 AC XY: 81 AN XY: 384342

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

African (AFR) AF: 0.00813 AC: 117 AN: 14384

American (AMR) AF: 0.000663 AC: 16 AN: 24128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19642

East Asian (EAS) AF: 0.00 AC: 0 AN: 32478

South Asian (SAS) AF: 0.0000688 AC: 4 AN: 58142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45640

Middle Eastern (MID) AF: 0.000239 AC: 1 AN: 4176

European-Non Finnish (NFE) AF: 0.0000200 AC: 10 AN: 501136

Other (OTH) AF: 0.000711 AC: 25 AN: 35170

⚠️ 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: 0.0142 AC: 1785 AN: 125634 Hom.: 28 Cov.: 30 AF XY: 0.0138 AC XY: 830 AN XY: 60160

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

African (AFR) AF: 0.0557 AC: 1683 AN: 30200

American (AMR) AF: 0.00603 AC: 68 AN: 11270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3328

East Asian (EAS) AF: 0.00 AC: 0 AN: 4180

South Asian (SAS) AF: 0.000271 AC: 1 AN: 3692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.000224 AC: 14 AN: 62472

Other (OTH) AF: 0.0110 AC: 19 AN: 1722

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.9
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: rs11476169; hg19: chr20-19867252;