20-19830470-A-T

Variant names:

• chr20-19830470-A-T
• rs2876544
• NM_018993.4:c.-37+30723A>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.-37+30723A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,042 control chromosomes in the GnomAD database, including 2,622 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 0.18 (2622 hom., cov: 32)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.-37+30723A>T		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001378238.1		c.-582+30723A>T		intron	N/A	NP_001365167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-37+30723A>T		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000944194.1		c.-37+30723A>T		intron	N/A	ENSP00000614253.1
	RIN2	ENST00000891327.1		c.-37+30723A>T		intron	N/A	ENSP00000561386.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26751 AN: 151924 Hom.: 2622 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.164

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

GnomAD4 genome AF: 0.176 AC: 26772 AN: 152042 Hom.: 2622 Cov.: 32 AF XY: 0.173 AC XY: 12829 AN XY: 74338

African (AFR) AF: 0.268 AC: 11127 AN: 41448

American (AMR) AF: 0.123 AC: 1884 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 516 AN: 3470

East Asian (EAS) AF: 0.124 AC: 638 AN: 5154

South Asian (SAS) AF: 0.165 AC: 796 AN: 4812

European-Finnish (FIN) AF: 0.129 AC: 1366 AN: 10584

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9841 AN: 67966

Other (OTH) AF: 0.162 AC: 343 AN: 2112

Alfa AF: 0.160 Hom.: 275

Bravo AF: 0.178

Asia WGS AF: 0.126 AC: 441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.38
PhyloP100		0.035

Splicing

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

Other links and lift over

dbSNP: rs2876544; hg19: chr20-19811114;