20-19886741-G-T

Variant names:

• chr20-19886741-G-T
• rs188049434
• NM_018993.4:c.-36-2825G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018993.4(RIN2):​c.-36-2825G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,394,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.964
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2825G>T		intron_variant	Intron 2 of 12	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2825G>T		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000138 AC: 2 AN: 144448 AF XY: 0.0000129

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394646 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 687948

African (AFR) AF: 0.00 AC: 0 AN: 31172

American (AMR) AF: 0.0000575 AC: 2 AN: 34764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25054

East Asian (EAS) AF: 0.00 AC: 0 AN: 35710

South Asian (SAS) AF: 0.00 AC: 0 AN: 78252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077620

Other (OTH) AF: 0.00 AC: 0 AN: 57998

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.18
DANN	Benign	0.77
PhyloP100		-0.96
PromoterAI		-0.26	Neutral

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

Other links and lift over

dbSNP: rs188049434; hg19: chr20-19867385;