20-19886593-C-CCTT

Variant names:

• chr20-19886593-C-CCTT
• rs767980692
• NM_018993.4:c.-36-2954_-36-2952dupCTT

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.-36-2954_-36-2952dupCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 786,122 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (15 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.157
• Publications: 0 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 20-19886593-C-CCTT is Benign according to our data. Variant chr20-19886593-C-CCTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1676376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00733 (1082/147540) while in subpopulation NFE AF = 0.0128 (859/67220). AF 95% confidence interval is 0.0121. There are 6 homozygotes in GnomAd4. There are 468 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.-36-2954_-36-2952dupCTT		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001378238.1		c.-581-2954_-581-2952dupCTT		intron	N/A	NP_001365167.1
	RIN2	NM_001242581.2		c.-77_-76insCTT		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.-36-2954_-36-2952dupCTT		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-205_-203dupCTT		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-205_-203dupCTT		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes AF: 0.00735 AC: 1084 AN: 147468 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00553

Gnomad EAS AF: 0.000397

Gnomad SAS AF: 0.000650

Gnomad FIN AF: 0.00581

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00343

GnomAD4 exome AF: 0.00310 AC: 1978 AN: 638582 Hom.: 15 Cov.: 9 AF XY: 0.00315 AC XY: 1061 AN XY: 336668

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

African (AFR) AF: 0.000772 AC: 11 AN: 14256

American (AMR) AF: 0.00116 AC: 28 AN: 24198

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 37 AN: 18262

East Asian (EAS) AF: 0.0000317 AC: 1 AN: 31516

South Asian (SAS) AF: 0.00652 AC: 348 AN: 53386

European-Finnish (FIN) AF: 0.00730 AC: 315 AN: 43178

Middle Eastern (MID) AF: 0.000274 AC: 1 AN: 3656

European-Non Finnish (NFE) AF: 0.00279 AC: 1167 AN: 418130

Other (OTH) AF: 0.00219 AC: 70 AN: 32000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00733 AC: 1082 AN: 147540 Hom.: 6 Cov.: 31 AF XY: 0.00652 AC XY: 468 AN XY: 71768

African (AFR) AF: 0.00189 AC: 75 AN: 39600

American (AMR) AF: 0.00398 AC: 58 AN: 14570

Ashkenazi Jewish (ASJ) AF: 0.00553 AC: 19 AN: 3436

East Asian (EAS) AF: 0.000398 AC: 2 AN: 5028

South Asian (SAS) AF: 0.000651 AC: 3 AN: 4608

European-Finnish (FIN) AF: 0.00581 AC: 57 AN: 9818

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.0128 AC: 859 AN: 67220

Other (OTH) AF: 0.00339 AC: 7 AN: 2064

Alfa AF: 0.00433 Hom.: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
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: rs767980692; hg19: chr20-19867237;