chr20-19886593-CCTT-C

Variant names:

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

Variant summary

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

The NM_018993.4(RIN2):​c.-36-2954_-36-2952delCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 786,188 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 0.00010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• 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, Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2954_-36-2952delCTT		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.-36-2954_-36-2952delCTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-205_-203delCTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2954_537-2952delCTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2954_618-2952delCTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000949 AC: 14 AN: 147514 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000743

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 111 AN: 638602 Hom.: 0 AF XY: 0.000166 AC XY: 56 AN XY: 336662

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

African (AFR) AF: 0.0000702 AC: 1 AN: 14254

American (AMR) AF: 0.000331 AC: 8 AN: 24202

Ashkenazi Jewish (ASJ) AF: 0.000274 AC: 5 AN: 18266

East Asian (EAS) AF: 0.0000317 AC: 1 AN: 31518

South Asian (SAS) AF: 0.000319 AC: 17 AN: 53356

European-Finnish (FIN) AF: 0.000232 AC: 10 AN: 43158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3654

European-Non Finnish (NFE) AF: 0.000146 AC: 61 AN: 418190

Other (OTH) AF: 0.000250 AC: 8 AN: 32004

⚠️ 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: 0.000102 AC: 15 AN: 147586 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 9 AN XY: 71788

African (AFR) AF: 0.000177 AC: 7 AN: 39600

American (AMR) AF: 0.000137 AC: 2 AN: 14572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5028

South Asian (SAS) AF: 0.00 AC: 0 AN: 4608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000743 AC: 5 AN: 67262

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16

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: rs767980692; hg19: chr20-19867237;