NM_018993.4:c.-36-17707G>A

Variant names:

• chr20-19871859-G-A
• rs6046396
• NM_018993.4:c.-36-17707G>A

Variant summary

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

The NM_018993.4(RIN2):​c.-36-17707G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 152,048 control chromosomes in the GnomAD database, including 35,544 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 0.68 (35543 hom., cov: 32)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• Publications: 15 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.701 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.-36-17707G>A		intron	N/A	NP_061866.1
	RIN2	NM_001378238.1		c.-581-17707G>A		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.-36-17707G>A		intron	N/A	ENSP00000255006.7
	RIN2	ENST00000616029.2	TSL:6	n.1208G>A		non_coding_transcript_exon	Exon 4 of 4
	RIN2	ENST00000432334.2	TSL:4	n.537-17707G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103735 AN: 151926 Hom.: 35520 Cov.: 32

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.654

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.683 AC: 103813 AN: 152046 Hom.: 35543 Cov.: 32 AF XY: 0.679 AC XY: 50484 AN XY: 74342

African (AFR) AF: 0.674 AC: 27944 AN: 41474

American (AMR) AF: 0.624 AC: 9548 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2211 AN: 3468

East Asian (EAS) AF: 0.669 AC: 3449 AN: 5152

South Asian (SAS) AF: 0.634 AC: 3059 AN: 4822

European-Finnish (FIN) AF: 0.697 AC: 7368 AN: 10564

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.707 AC: 48025 AN: 67962

Other (OTH) AF: 0.654 AC: 1379 AN: 2108

Alfa AF: 0.693 Hom.: 154746

Bravo AF: 0.677

Asia WGS AF: 0.624 AC: 2170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.46
PhyloP100		-0.026

Splicing

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

Other links and lift over

dbSNP: rs6046396; hg19: chr20-19852503;