20-19886398-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018993.4(RIN2):c.-36-3168C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 328,602 control chromosomes in the GnomAD database, including 9,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5049 hom., cov: 31)
  • Exomes 𝑓: 0.21 (4051 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.905

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 20-19886398-C-T is Benign according to our data. Variant chr20-19886398-C-T is described in ClinVar as [Benign]. Clinvar id is 683996.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.-36-3168C>T		intron_variant		ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-3168C>T		intron_variant		2	NM_018993.4	P1
RIN2	ENST00000432334.2	n.537-3168C>T		intron_variant, non_coding_transcript_variant		4
RIN2	ENST00000648165.1	n.618-3168C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37569 AN: 151884 Hom.: 5040 Cov.: 31

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.207 AC: 36560 AN: 176600 Hom.: 4051 AF XY: 0.207 AC XY: 18693 AN XY: 90204

Gnomad4 AFR exome AF: 0.350

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.267

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.247 AC: 37611 AN: 152002 Hom.: 5049 Cov.: 31 AF XY: 0.248 AC XY: 18450 AN XY: 74300

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.236

Alfa AF: 0.198 Hom.: 4176

Bravo AF: 0.254

Asia WGS AF: 0.294 AC: 1025 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	7.9
Dann	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6132239; hg19: chr20-19867042;