20-19886612-CTTTTTTTTTTT-CTTTTTTTTTTTTTTTT

Variant names:

• chr20-19886612-C-CTTTTT
• rs11362637
• NM_018993.4:c.-36-2939_-36-2935dupTTTTT

Variant summary

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

The NM_018993.4(RIN2):​c.-36-2939_-36-2935dupTTTTT 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 0.00023 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00091 (1 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.-36-2939_-36-2935dupTTTTT		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.-36-2939_-36-2935dupTTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-190_-186dupTTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2939_537-2935dupTTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2939_618-2935dupTTTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000226 AC: 26 AN: 115224 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000443

Gnomad AMI AF: 0.00126

Gnomad AMR AF: 0.000184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000293

Gnomad FIN AF: 0.000214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000122

Gnomad OTH AF: 0.000653

GnomAD4 exome AF: 0.000912 AC: 370 AN: 405558 Hom.: 1 Cov.: 0 AF XY: 0.000995 AC XY: 218 AN XY: 219122

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

African (AFR) AF: 0.00152 AC: 13 AN: 8536

American (AMR) AF: 0.00184 AC: 30 AN: 16332

Ashkenazi Jewish (ASJ) AF: 0.000386 AC: 5 AN: 12956

East Asian (EAS) AF: 0.00160 AC: 39 AN: 24368

South Asian (SAS) AF: 0.00213 AC: 86 AN: 40292

European-Finnish (FIN) AF: 0.000366 AC: 12 AN: 32818

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

European-Non Finnish (NFE) AF: 0.000690 AC: 170 AN: 246442

Other (OTH) AF: 0.000652 AC: 14 AN: 21486

⚠️ 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: 0.000226 AC: 26 AN: 115212 Hom.: 0 Cov.: 0 AF XY: 0.000258 AC XY: 14 AN XY: 54182

⚠️ 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: 29406

American (AMR) AF: 0.000183 AC: 2 AN: 10900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3010

East Asian (EAS) AF: 0.00 AC: 0 AN: 4056

South Asian (SAS) AF: 0.000295 AC: 1 AN: 3390

European-Finnish (FIN) AF: 0.000214 AC: 1 AN: 4676

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

European-Non Finnish (NFE) AF: 0.000122 AC: 7 AN: 57232

Other (OTH) AF: 0.000649 AC: 1 AN: 1540

⚠️ 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: 0.000717 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;