20-19886612-CTTTTTTTTTTT-CTT

Variant names:

• chr20-19886612-CTTTTTTTTT-C
• rs11362637
• NM_018993.4:c.-36-2943_-36-2935delTTTTTTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_018993.4(RIN2):​c.-36-2943_-36-2935delTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 405,686 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: not found (cov: 0)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000394 (16/405686) while in subpopulation AFR AF = 0.00082 (7/8538). AF 95% confidence interval is 0.000384. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

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.-36-2943_-36-2935delTTTTTTTTT		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001378238.1		c.-581-2943_-581-2935delTTTTTTTTT		intron	N/A	NP_001365167.1
	RIN2	NM_001242581.2		c.-57_-49delTTTTTTTTT		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.-36-2943_-36-2935delTTTTTTTTT		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-194_-186delTTTTTTTTT		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-194_-186delTTTTTTTTT		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000394 AC: 16 AN: 405686 Hom.: 0 AF XY: 0.0000365 AC XY: 8 AN XY: 219208

African (AFR) AF: 0.000820 AC: 7 AN: 8538

American (AMR) AF: 0.0000612 AC: 1 AN: 16344

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

East Asian (EAS) AF: 0.000123 AC: 3 AN: 24372

South Asian (SAS) AF: 0.0000744 AC: 3 AN: 40324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2328

European-Non Finnish (NFE) AF: 0.00000811 AC: 2 AN: 246514

Other (OTH) AF: 0.00 AC: 0 AN: 21488

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20

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;