20-19886489-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.-36-3077C>T		intron_variant		ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-3077C>T		intron_variant		2	NM_018993.4	P1
RIN2	ENST00000432334.2	n.537-3077C>T		intron_variant, non_coding_transcript_variant		4
RIN2	ENST00000648165.1	n.618-3077C>T		intron_variant, non_coding_transcript_variant
RIN2	ENST00000648440.1			upstream_gene_variant				P1

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

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000348

Gnomad4 NFE exome AF: 0.0000876

Gnomad4 OTH exome AF: 0.00159

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

Gnomad4 AFR AF: 0.0278

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00596 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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	11
Dann	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59276130; hg19: chr20-19867133;