chr20-19886489-C-T

Variant names:

• chr20-19886489-C-T
• rs59276130
• NM_018993.4:c.-36-3077C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018993.4(RIN2):​c.-36-3077C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 543,644 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (25 hom., cov: 31)
  • Exomes 𝑓: 0.00097 (4 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0700
• 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, Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 20-19886489-C-T is Benign according to our data. Variant chr20-19886489-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1218108.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00787 (1196/151908) while in subpopulation AFR AF = 0.0278 (1146/41268). AF 95% confidence interval is 0.0264. There are 25 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-3077C>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.-36-3077C>T		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000432334.2	n.537-3077C>T		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-3077C>T		intron_variant	Intron 3 of 3
RIN2	ENST00000648440.1	c.-328C>T		upstream_gene_variant				ENSP00000498085.1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1175 AN: 151790 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.000973 AC: 381 AN: 391736 Hom.: 4 Cov.: 0 AF XY: 0.000881 AC XY: 182 AN XY: 206568

African (AFR) AF: 0.0283 AC: 297 AN: 10502

American (AMR) AF: 0.00164 AC: 25 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12102

East Asian (EAS) AF: 0.00 AC: 0 AN: 28988

South Asian (SAS) AF: 0.00 AC: 0 AN: 31444

European-Finnish (FIN) AF: 0.0000348 AC: 1 AN: 28768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1724

European-Non Finnish (NFE) AF: 0.0000876 AC: 21 AN: 239704

Other (OTH) AF: 0.00159 AC: 37 AN: 23222

GnomAD4 genome AF: 0.00787 AC: 1196 AN: 151908 Hom.: 25 Cov.: 31 AF XY: 0.00789 AC XY: 586 AN XY: 74264

African (AFR) AF: 0.0278 AC: 1146 AN: 41268

American (AMR) AF: 0.00223 AC: 34 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68012

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00632 Hom.: 3

Bravo AF: 0.00814

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 12, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		0.070
PromoterAI		-0.31	Neutral

Splicing

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

Other links and lift over

dbSNP: rs59276130; hg19: chr20-19867133;