20-19870811-T-G

Variant names:

• chr20-19870811-T-G
• rs4813376
• NM_018993.4:c.-36-18755T>G

Variant summary

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

The NM_018993.4(RIN2):​c.-36-18755T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 152,106 control chromosomes in the GnomAD database, including 55,976 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 0.86 (55976 hom., cov: 31)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.617
• 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=-0.98).
• 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.-36-18755T>G		intron	N/A	NP_061866.1
	RIN2	NM_001378238.1		c.-581-18755T>G		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.-36-18755T>G		intron	N/A	ENSP00000255006.7
	RIN2	ENST00000432334.2	TSL:4	n.537-18755T>G		intron	N/A
	RIN2	ENST00000616029.2	TSL:6	n.359-33T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130188 AN: 151988 Hom.: 55928 Cov.: 31

Gnomad AFR AF: 0.913

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.832

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.851

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.846

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

GnomAD4 genome AF: 0.857 AC: 130298 AN: 152106 Hom.: 55976 Cov.: 31 AF XY: 0.856 AC XY: 63634 AN XY: 74348

African (AFR) AF: 0.913 AC: 37871 AN: 41492

American (AMR) AF: 0.870 AC: 13304 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 2888 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4850 AN: 5170

South Asian (SAS) AF: 0.851 AC: 4093 AN: 4808

European-Finnish (FIN) AF: 0.800 AC: 8462 AN: 10578

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.824 AC: 56003 AN: 67984

Other (OTH) AF: 0.847 AC: 1788 AN: 2112

Alfa AF: 0.837 Hom.: 167924

Bravo AF: 0.865

Asia WGS AF: 0.875 AC: 3045 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	6.9
DANN	Benign	0.66
PhyloP100		0.62

Splicing

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

Other links and lift over

dbSNP: rs4813376; hg19: chr20-19851455;