20-19886612-C-T

Variant names:

• chr20-19886612-C-T
• rs6112633
• NM_018993.4:c.-36-2954C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018993.4(RIN2):​c.-36-2954C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 16)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.852
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-19886612-C-T is Benign according to our data. Variant chr20-19886612-C-T is described in ClinVar as [Benign]. Clinvar id is 1228223.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2954C>T		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.-36-2954C>T		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-205C>T		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2954C>T		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2954C>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 1731 AN: 115190 Hom.: 61 Cov.: 16

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00541

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: 0.000279

Gnomad OTH AF: 0.0150

GnomAD4 exome AF: 0.000382 AC: 155 AN: 405554 Hom.: 0 Cov.: 6 AF XY: 0.000374 AC XY: 82 AN XY: 219132

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

African (AFR) AF: 0.0110 AC: 93 AN: 8480

American (AMR) AF: 0.000918 AC: 15 AN: 16336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12956

East Asian (EAS) AF: 0.0000821 AC: 2 AN: 24370

South Asian (SAS) AF: 0.000174 AC: 7 AN: 40310

European-Finnish (FIN) AF: 0.000122 AC: 4 AN: 32824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2328

European-Non Finnish (NFE) AF: 0.0000852 AC: 21 AN: 246464

Other (OTH) AF: 0.000605 AC: 13 AN: 21486

⚠️ 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: 0.0150 AC: 1732 AN: 115178 Hom.: 62 Cov.: 16 AF XY: 0.0147 AC XY: 796 AN XY: 54180

African (AFR) AF: 0.0557 AC: 1634 AN: 29338

American (AMR) AF: 0.00532 AC: 58 AN: 10900

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4058

South Asian (SAS) AF: 0.000295 AC: 1 AN: 3388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4676

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

European-Non Finnish (NFE) AF: 0.000279 AC: 16 AN: 57262

Other (OTH) AF: 0.0149 AC: 23 AN: 1540

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.53
DANN	Benign	0.44
PhyloP100		-0.85
PromoterAI		-0.074	Neutral
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: rs6112633; hg19: chr20-19867256; COSMIC: COSV54788751; COSMIC: COSV54788751;