20-19886612-CTTTTTTTTTTT-CTTTTTTTTTTTTTT

Variant names:

• chr20-19886612-C-CTTT
• rs11362637
• NM_018993.4:c.-36-2937_-36-2935dupTTT

Variant summary

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

The NM_018993.4(RIN2):​c.-36-2937_-36-2935dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.844
• Publications: 2 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.-36-2937_-36-2935dupTTT		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.-36-2937_-36-2935dupTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-188_-186dupTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2937_537-2935dupTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2937_618-2935dupTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000686 AC: 79 AN: 115176 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000443

Gnomad AMI AF: 0.00126

Gnomad AMR AF: 0.000275

Gnomad ASJ AF: 0.00200

Gnomad EAS AF: 0.000245

Gnomad SAS AF: 0.000586

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000927

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00161 AC: 654 AN: 405432 Hom.: 0 Cov.: 0 AF XY: 0.00168 AC XY: 368 AN XY: 219068

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

African (AFR) AF: 0.00223 AC: 19 AN: 8528

American (AMR) AF: 0.00324 AC: 53 AN: 16334

Ashkenazi Jewish (ASJ) AF: 0.00139 AC: 18 AN: 12956

East Asian (EAS) AF: 0.00156 AC: 38 AN: 24356

South Asian (SAS) AF: 0.00355 AC: 143 AN: 40274

European-Finnish (FIN) AF: 0.000579 AC: 19 AN: 32806

Middle Eastern (MID) AF: 0.000430 AC: 1 AN: 2328

European-Non Finnish (NFE) AF: 0.00132 AC: 326 AN: 246376

Other (OTH) AF: 0.00172 AC: 37 AN: 21474

⚠️ 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: 0.000686 AC: 79 AN: 115164 Hom.: 0 Cov.: 0 AF XY: 0.000812 AC XY: 44 AN XY: 54154

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

African (AFR) AF: 0.000442 AC: 13 AN: 29402

American (AMR) AF: 0.000275 AC: 3 AN: 10896

Ashkenazi Jewish (ASJ) AF: 0.00200 AC: 6 AN: 3004

East Asian (EAS) AF: 0.000246 AC: 1 AN: 4058

South Asian (SAS) AF: 0.000590 AC: 2 AN: 3390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.000927 AC: 53 AN: 57196

Other (OTH) AF: 0.00 AC: 0 AN: 1538

⚠️ 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.: 309

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.84

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;