rs4814920

Variant names:

• chr20-19885312-A-T
• rs4814920
• NM_018993.4:c.-36-4254A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018993.4(RIN2):​c.-36-4254A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 152,136 control chromosomes in the GnomAD database, including 51,715 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (51715 hom., cov: 31)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.81
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018993.4. 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.-36-4254A>T		intron	N/A	NP_061866.1
	RIN2	NM_001378238.1		c.-581-4254A>T		intron	N/A	NP_001365167.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-4254A>T		intron	N/A	ENSP00000255006.7
	RIN2	ENST00000944194.1		c.-36-4254A>T		intron	N/A	ENSP00000614253.1
	RIN2	ENST00000891327.1		c.-36-4254A>T		intron	N/A	ENSP00000561386.1

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125207 AN: 152018 Hom.: 51668 Cov.: 31

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.939

Gnomad SAS AF: 0.848

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.863

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.822

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.824 AC: 125312 AN: 152136 Hom.: 51715 Cov.: 31 AF XY: 0.824 AC XY: 61250 AN XY: 74346

African (AFR) AF: 0.811 AC: 33650 AN: 41470

American (AMR) AF: 0.856 AC: 13086 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 2883 AN: 3470

East Asian (EAS) AF: 0.938 AC: 4856 AN: 5176

South Asian (SAS) AF: 0.848 AC: 4092 AN: 4826

European-Finnish (FIN) AF: 0.791 AC: 8359 AN: 10574

Middle Eastern (MID) AF: 0.870 AC: 254 AN: 292

European-Non Finnish (NFE) AF: 0.818 AC: 55626 AN: 68012

Other (OTH) AF: 0.824 AC: 1740 AN: 2112

Alfa AF: 0.815 Hom.: 6261

Bravo AF: 0.829

Asia WGS AF: 0.869 AC: 3021 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.34
DANN	Benign	0.38
PhyloP100		-1.8

Splicing

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

Other links and lift over

dbSNP: rs4814920; hg19: chr20-19865956;