chr20-19886612-CTT-C

Variant names:

• chr20-19886612-CTT-C
• rs11362637
• NM_018993.4:c.-36-2936_-36-2935delTT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_018993.4(RIN2):​c.-36-2936_-36-2935delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 506,436 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 0)
  • Exomes 𝑓: 0.13 (1 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0580
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the NFE (0.143) population. However there is too low homozygotes in high coverage region: (expected more than 1372, got 1).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000599 (69/115246) while in subpopulation AFR AF = 0.000748 (22/29424). AF 95% confidence interval is 0.000506. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2936_-36-2935delTT		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.-36-2936_-36-2935delTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-187_-186delTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2936_537-2935delTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2936_618-2935delTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000590 AC: 68 AN: 115258 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000715

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000734

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000737

Gnomad SAS AF: 0.000586

Gnomad FIN AF: 0.00257

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000653

GnomAD4 exome AF: 0.135 AC: 52666 AN: 391190 Hom.: 1 AF XY: 0.133 AC XY: 28204 AN XY: 211316

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

African (AFR) AF: 0.110 AC: 902 AN: 8234

American (AMR) AF: 0.130 AC: 2049 AN: 15802

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 1429 AN: 12494

East Asian (EAS) AF: 0.140 AC: 3263 AN: 23276

South Asian (SAS) AF: 0.106 AC: 4127 AN: 39072

European-Finnish (FIN) AF: 0.109 AC: 3469 AN: 31730

Middle Eastern (MID) AF: 0.0828 AC: 189 AN: 2282

European-Non Finnish (NFE) AF: 0.144 AC: 34310 AN: 237664

Other (OTH) AF: 0.142 AC: 2928 AN: 20636

⚠️ 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: 0.000599 AC: 69 AN: 115246 Hom.: 0 Cov.: 0 AF XY: 0.000554 AC XY: 30 AN XY: 54194

African (AFR) AF: 0.000748 AC: 22 AN: 29424

American (AMR) AF: 0.000734 AC: 8 AN: 10902

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

East Asian (EAS) AF: 0.000740 AC: 3 AN: 4056

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

European-Finnish (FIN) AF: 0.00257 AC: 12 AN: 4672

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

European-Non Finnish (NFE) AF: 0.000367 AC: 21 AN: 57246

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

Alfa AF: 0.00 Hom.: 309

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.058
Mutation Taster		=300/0	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;