20-19886612-CTTTTTTTTTTT-CTTTTTTTTTTTTTTT

Variant names:

• chr20-19886612-C-CTTTT
• rs11362637
• NM_018993.4:c.-36-2938_-36-2935dupTTTT

Variant summary

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

The NM_018993.4(RIN2):​c.-36-2938_-36-2935dupTTTT 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 0.00062 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (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.-36-2938_-36-2935dupTTTT		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.-36-2938_-36-2935dupTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-189_-186dupTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2938_537-2935dupTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2938_618-2935dupTTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000616 AC: 71 AN: 115238 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000982

Gnomad SAS AF: 0.000879

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000419

Gnomad OTH AF: 0.000653

GnomAD4 exome AF: 0.00111 AC: 449 AN: 405444 Hom.: 0 Cov.: 0 AF XY: 0.00114 AC XY: 250 AN XY: 219070

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

African (AFR) AF: 0.00199 AC: 17 AN: 8542

American (AMR) AF: 0.00165 AC: 27 AN: 16324

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 13 AN: 12948

East Asian (EAS) AF: 0.00177 AC: 43 AN: 24362

South Asian (SAS) AF: 0.00246 AC: 99 AN: 40278

European-Finnish (FIN) AF: 0.000213 AC: 7 AN: 32820

Middle Eastern (MID) AF: 0.000430 AC: 1 AN: 2326

European-Non Finnish (NFE) AF: 0.000885 AC: 218 AN: 246364

Other (OTH) AF: 0.00112 AC: 24 AN: 21480

⚠️ 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: 0.000616 AC: 71 AN: 115238 Hom.: 0 Cov.: 0 AF XY: 0.000683 AC XY: 37 AN XY: 54180

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

African (AFR) AF: 0.00119 AC: 35 AN: 29370

American (AMR) AF: 0.000367 AC: 4 AN: 10896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3008

East Asian (EAS) AF: 0.000982 AC: 4 AN: 4074

South Asian (SAS) AF: 0.000879 AC: 3 AN: 3414

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.000419 AC: 24 AN: 57248

Other (OTH) AF: 0.000653 AC: 1 AN: 1532

⚠️ 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.

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;