20-19886612-CTTTTTTTTTTT-CTTTTTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018993.4(RIN2):​c.-36-2938_-36-2935delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 514,470 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: 0.011 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400
• 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 2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.0112) population. However there is too low homozygotes in high coverage region: (expected more than 9, got 0).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2938_-36-2935delTTTT		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_-36-2935delTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-189_-186delTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2938_537-2935delTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2938_618-2935delTTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000174 AC: 2 AN: 115272 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000293

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0108 AC: 4328 AN: 399198 Hom.: 0 AF XY: 0.0108 AC XY: 2331 AN XY: 215596

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

African (AFR) AF: 0.00866 AC: 73 AN: 8432

American (AMR) AF: 0.0114 AC: 182 AN: 15998

Ashkenazi Jewish (ASJ) AF: 0.00941 AC: 120 AN: 12758

East Asian (EAS) AF: 0.00994 AC: 238 AN: 23954

South Asian (SAS) AF: 0.0106 AC: 421 AN: 39636

European-Finnish (FIN) AF: 0.00735 AC: 238 AN: 32382

Middle Eastern (MID) AF: 0.00521 AC: 12 AN: 2304

European-Non Finnish (NFE) AF: 0.0115 AC: 2800 AN: 242574

Other (OTH) AF: 0.0115 AC: 244 AN: 21160

⚠️ 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: 0.0000174 AC: 2 AN: 115272 Hom.: 0 Cov.: 0 AF XY: 0.0000369 AC XY: 2 AN XY: 54188

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

African (AFR) AF: 0.0000340 AC: 1 AN: 29384

American (AMR) AF: 0.00 AC: 0 AN: 10896

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

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

South Asian (SAS) AF: 0.000293 AC: 1 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: 0.00 AC: 0 AN: 57264

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 = 0.000000), 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		-0.040
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11362637; hg19: chr20-19867256;