20-19886612-CTTTTTTTTTTT-CTTTTT

Variant names:

• chr20-19886612-CTTTTTT-C
• rs11362637
• NM_018993.4:c.-36-2940_-36-2935delTTTTTT

Variant summary

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

The NM_018993.4(RIN2):​c.-36-2940_-36-2935delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 519,894 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: 𝑓 0.000017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00086 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.204
• 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.-36-2940_-36-2935delTTTTTT		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.-36-2940_-36-2935delTTTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-191_-186delTTTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2940_537-2935delTTTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2940_618-2935delTTTTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000173 AC: 2 AN: 115278 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000175

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000855 AC: 346 AN: 404616 Hom.: 0 AF XY: 0.000787 AC XY: 172 AN XY: 218628

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

African (AFR) AF: 0.000586 AC: 5 AN: 8530

American (AMR) AF: 0.000675 AC: 11 AN: 16300

Ashkenazi Jewish (ASJ) AF: 0.000929 AC: 12 AN: 12916

East Asian (EAS) AF: 0.000535 AC: 13 AN: 24316

South Asian (SAS) AF: 0.000572 AC: 23 AN: 40190

European-Finnish (FIN) AF: 0.000734 AC: 24 AN: 32716

Middle Eastern (MID) AF: 0.000860 AC: 2 AN: 2326

European-Non Finnish (NFE) AF: 0.000960 AC: 236 AN: 245882

Other (OTH) AF: 0.000933 AC: 20 AN: 21440

⚠️ 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: 0.0000173 AC: 2 AN: 115278 Hom.: 0 Cov.: 0 AF XY: 0.0000185 AC XY: 1 AN XY: 54192

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

African (AFR) AF: 0.00 AC: 0 AN: 29384

American (AMR) AF: 0.00 AC: 0 AN: 10898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3012

East Asian (EAS) AF: 0.00 AC: 0 AN: 4074

South Asian (SAS) AF: 0.00 AC: 0 AN: 3414

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

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

European-Non Finnish (NFE) AF: 0.0000175 AC: 1 AN: 57268

Other (OTH) AF: 0.00 AC: 0 AN: 1532

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.002339), 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		0.20

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; COSMIC: COSV54791055; COSMIC: COSV54791055;