chr20-19935125-C-T

Variant names:

• chr20-19935125-C-T
• rs181853315
• NM_018993.4:c.84C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001378238.1(RIN2):​c.-462C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,602,132 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0091 (92 hom.)
• Consequence: RIN2 NM_001378238.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.784
• Publications: 9 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 20-19935125-C-T is Benign according to our data. Variant chr20-19935125-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00647 (985/152206) while in subpopulation NFE AF = 0.0092 (626/68014). AF 95% confidence interval is 0.00861. There are 8 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378238.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.84C>T	p.Ile28Ile	synonymous	Exon 4 of 13	NP_061866.1
	RIN2	NM_001378238.1		c.-462C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	NP_001365167.1
	RIN2	NM_001242581.2		c.231C>T	p.Ile77Ile	synonymous	Exon 3 of 12	NP_001229510.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.84C>T	p.Ile28Ile	synonymous	Exon 4 of 13	ENSP00000255006.7
	RIN2	ENST00000440354.2	TSL:1	c.84C>T	p.Ile28Ile	synonymous	Exon 2 of 8	ENSP00000391239.2
	RIN2	ENST00000484638.1	TSL:1	n.1C>T		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 985 AN: 152088 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00689

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00669 AC: 1549 AN: 231368 AF XY: 0.00667

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00603

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00977

GnomAD4 exome AF: 0.00911 AC: 13203 AN: 1449926 Hom.: 92 Cov.: 30 AF XY: 0.00904 AC XY: 6506 AN XY: 719944

African (AFR) AF: 0.00138 AC: 46 AN: 33246

American (AMR) AF: 0.00313 AC: 135 AN: 43066

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 419 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39174

South Asian (SAS) AF: 0.00189 AC: 158 AN: 83756

European-Finnish (FIN) AF: 0.00661 AC: 348 AN: 52676

Middle Eastern (MID) AF: 0.00747 AC: 43 AN: 5754

European-Non Finnish (NFE) AF: 0.0104 AC: 11488 AN: 1106324

Other (OTH) AF: 0.00943 AC: 566 AN: 60018

GnomAD4 genome AF: 0.00647 AC: 985 AN: 152206 Hom.: 8 Cov.: 31 AF XY: 0.00625 AC XY: 465 AN XY: 74412

African (AFR) AF: 0.00190 AC: 79 AN: 41528

American (AMR) AF: 0.00655 AC: 100 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4820

European-Finnish (FIN) AF: 0.00689 AC: 73 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00920 AC: 626 AN: 68014

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00833 Hom.: 0

Bravo AF: 0.00650

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	RIN2 syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=99/1	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: rs181853315; hg19: chr20-19915769; COSMIC: COSV99658025;