NM_018993.4:c.-37+44002C>T

Variant names:

• chr20-19843749-C-T
• rs10485594
• NM_018993.4:c.-37+44002C>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+44002C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 152,014 control chromosomes in the GnomAD database, including 288 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 0.055 (288 hom., cov: 32)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.684
• Publications: 3 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.159 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.-37+44002C>T		intron	N/A	NP_061866.1
	RIN2	NM_001378238.1		c.-582+44002C>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.-37+44002C>T		intron	N/A	ENSP00000255006.7
	RIN2	ENST00000432334.2	TSL:4	n.536+28451C>T		intron	N/A
	RIN2	ENST00000616029.2	TSL:6	n.359-27095C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8376 AN: 151898 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.0925

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.0604

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0656

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

GnomAD4 genome AF: 0.0551 AC: 8376 AN: 152014 Hom.: 288 Cov.: 32 AF XY: 0.0576 AC XY: 4279 AN XY: 74306

African (AFR) AF: 0.0192 AC: 797 AN: 41456

American (AMR) AF: 0.0566 AC: 864 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3470

East Asian (EAS) AF: 0.0923 AC: 478 AN: 5176

South Asian (SAS) AF: 0.169 AC: 811 AN: 4808

European-Finnish (FIN) AF: 0.0604 AC: 637 AN: 10542

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0637 AC: 4329 AN: 67978

Other (OTH) AF: 0.0644 AC: 136 AN: 2112

Alfa AF: 0.0661 Hom.: 259

Bravo AF: 0.0511

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.83
DANN	Benign	0.64
PhyloP100		-0.68

Splicing

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

Other links and lift over

dbSNP: rs10485594; hg19: chr20-19824393;