20-19886676-G-T

Position:

• chr20-19886676-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242581.2(RIN2):​c.7G>T​(p.Asp3Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: RIN2 NM_001242581.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.367

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07526508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2890G>T		intron_variant		ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2890G>T		intron_variant		2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440	c.-141G>T		5_prime_UTR_variant	1/12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2890G>T		intron_variant		4
RIN2	ENST00000648165.1	n.618-2890G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2021

This sequence change replaces aspartic acid with tyrosine at codon 3 of the RIN2 protein (p.(Asp3Tyr). The RIN2 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001242581.1, and corresponds to NM_018993.3:c.-2926G>T in the primary transcript. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with RIN2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.7
DANN	Benign	0.96
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.0050
Sift	Pathogenic	0.0	D
Vest4		0.14
MutPred		0.20		Gain of sheet (P = 0.0125);
MVP		0.15
MPC		0.78
ClinPred		0.20	T
GERP RS		0.54
gMVP		0.045

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-19867320;