20-19935125-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378238.1(RIN2):​c.-462C>G 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 0.00000069 in 1,450,030 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIN2 NM_001378238.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.784
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>G	p.Ile28Met	missense	Exon 4 of 13	NP_061866.1
	RIN2	NM_001378238.1		c.-462C>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	NP_001365167.1
	RIN2	NM_001242581.2		c.231C>G	p.Ile77Met	missense	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>G	p.Ile28Met	missense	Exon 4 of 13	ENSP00000255006.7
	RIN2	ENST00000440354.2	TSL:1	c.84C>G	p.Ile28Met	missense	Exon 2 of 8	ENSP00000391239.2
	RIN2	ENST00000484638.1	TSL:1	n.1C>G		non_coding_transcript_exon	Exon 1 of 9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450030 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719974

African (AFR) AF: 0.0000301 AC: 1 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 43066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 83756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106422

Other (OTH) AF: 0.00 AC: 0 AN: 60020

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.78
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.64		Loss of loop (P = 0.0374)
MVP		0.60
MPC		0.60
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.27
gMVP		0.35
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;