NM_018993.4:c.-36-2935dupT

Variant names:

• chr20-19886612-C-CT
• rs11362637
• NM_018993.4:c.-36-2935dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018993.4(RIN2):​c.-36-2935dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1241 hom., cov: 0)
  • Exomes 𝑓: 0.045 (11 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 20-19886612-C-CT is Benign according to our data. Variant chr20-19886612-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1276958.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018993.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.-36-2935dupT		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001378238.1		c.-581-2935dupT		intron	N/A	NP_001365167.1
	RIN2	NM_001242581.2		c.-58_-57insT		upstream_gene	N/A	NP_001229510.1	Q8WYP3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-2935dupT		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-186dupT		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-186dupT		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 15920 AN: 115156 Hom.: 1242 Cov.: 0

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0949

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.0453 AC: 18255 AN: 403032 Hom.: 11 Cov.: 0 AF XY: 0.0443 AC XY: 9650 AN XY: 217770

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

African (AFR) AF: 0.0727 AC: 613 AN: 8432

American (AMR) AF: 0.0672 AC: 1089 AN: 16214

Ashkenazi Jewish (ASJ) AF: 0.0426 AC: 548 AN: 12878

East Asian (EAS) AF: 0.0817 AC: 1969 AN: 24104

South Asian (SAS) AF: 0.0440 AC: 1765 AN: 40140

European-Finnish (FIN) AF: 0.0328 AC: 1072 AN: 32656

Middle Eastern (MID) AF: 0.0301 AC: 70 AN: 2324

European-Non Finnish (NFE) AF: 0.0410 AC: 10048 AN: 244938

Other (OTH) AF: 0.0506 AC: 1081 AN: 21346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.138 AC: 15924 AN: 115142 Hom.: 1241 Cov.: 0 AF XY: 0.140 AC XY: 7600 AN XY: 54146

African (AFR) AF: 0.194 AC: 5697 AN: 29370

American (AMR) AF: 0.197 AC: 2145 AN: 10884

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 307 AN: 3006

East Asian (EAS) AF: 0.221 AC: 897 AN: 4056

South Asian (SAS) AF: 0.131 AC: 443 AN: 3382

European-Finnish (FIN) AF: 0.0693 AC: 324 AN: 4672

Middle Eastern (MID) AF: 0.133 AC: 28 AN: 210

European-Non Finnish (NFE) AF: 0.101 AC: 5786 AN: 57234

Other (OTH) AF: 0.144 AC: 222 AN: 1538

Alfa AF: 0.0341 Hom.: 309

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.84
Mutation Taster		=300/0	polymorphism (auto)

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;