20-19886740-C-T

Position:

• chr20-19886740-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018993.4(RIN2):​c.-36-2826C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,545,556 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0050 (41 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.304

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043200552).
• BP6: Variant 20-19886740-C-T is Benign according to our data. Variant chr20-19886740-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 444566.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 = 0.00292 (444/151844) while in subpopulation NFE AF= 0.00539 (366/67964). AF 95% confidence interval is 0.00493. There are 1 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.-36-2826C>T		intron_variant		ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2826C>T		intron_variant		2	NM_018993.4	P1
RIN2	ENST00000648440.1	c.-77C>T		5_prime_UTR_variant	1/12			P1
RIN2	ENST00000432334.2	n.537-2826C>T		intron_variant, non_coding_transcript_variant		4
RIN2	ENST00000648165.1	n.618-2826C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 444 AN: 151728 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000872

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00538

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00242 AC: 355 AN: 146716 Hom.: 3 AF XY: 0.00233 AC XY: 183 AN XY: 78554

Gnomad AFR exome AF: 0.000427

Gnomad AMR exome AF: 0.000593

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00137

Gnomad SAS exome AF: 0.0000470

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00503 AC: 7015 AN: 1393712 Hom.: 41 Cov.: 30 AF XY: 0.00491 AC XY: 3378 AN XY: 687434

Gnomad4 AFR exome AF: 0.000803

Gnomad4 AMR exome AF: 0.000755

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.000532

Gnomad4 SAS exome AF: 0.000167

Gnomad4 FIN exome AF: 0.00194

Gnomad4 NFE exome AF: 0.00616

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.00292 AC: 444 AN: 151844 Hom.: 1 Cov.: 29 AF XY: 0.00270 AC XY: 200 AN XY: 74164

Gnomad4 AFR AF: 0.000869

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00124

Gnomad4 NFE AF: 0.00539

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00425 Hom.: 0

Bravo AF: 0.00294

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.00118 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	RIN2: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2017

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. -

RIN2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.4
DANN	Benign	0.85
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0053	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.0080
Sift	Pathogenic	0.0	D
Vest4		0.076
MVP		0.17
MPC		0.20
ClinPred		0.028	T
GERP RS		-7.0
gMVP		0.036

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

Publications

LitVar

Other links and lift over

dbSNP: rs183028833; hg19: chr20-19867384;