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, Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2943_-36-2935delTTTTTTTTT		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.-36-2943_-36-2935delTTTTTTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-194_-186delTTTTTTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2943_537-2935delTTTTTTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2943_618-2935delTTTTTTTTT		intron_variant	Intron 3 of 3

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 v4.3

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;