20-19757520-C-T

Variant names:

• chr20-19757520-C-T
• rs910983
• ENST00000598007.2:n.518G>A

Variant summary

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

The ENST00000598007.2(ENSG00000268628):​n.518G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 152,248 control chromosomes in the GnomAD database, including 24,522 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 0.53 (24514 hom., cov: 35)
  • Exomes 𝑓: 0.57 (8 hom.)
• Consequence: ENSG00000268628 ENST00000598007.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.30
• Publications: 4 publications found

Genes affected

ENSG00000268628 (HGNC:):

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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.687 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	XM_017027887.2	c.-793C>T		upstream_gene_variant			XP_016883376.1
RIN2	XM_017027888.2	c.-865C>T		upstream_gene_variant			XP_016883377.1
RIN2	XM_047440212.1	c.-941C>T		upstream_gene_variant			XP_047296168.1
RIN2	XM_047440213.1	c.-869C>T		upstream_gene_variant			XP_047296169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000268628	ENST00000598007.2	n.518G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000268628	ENST00000827038.1	n.247-332G>A		intron_variant	Intron 1 of 1
RIN2	ENST00000432334.2	n.-86C>T		upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80422 AN: 152086 Hom.: 24515 Cov.: 35

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.461

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.539

GnomAD4 exome AF: 0.568 AC: 25 AN: 44 Hom.: 8 Cov.: 0 AF XY: 0.625 AC XY: 20 AN XY: 32

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.571 AC: 24 AN: 42

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.528 AC: 80426 AN: 152204 Hom.: 24514 Cov.: 35 AF XY: 0.538 AC XY: 40058 AN XY: 74436

African (AFR) AF: 0.207 AC: 8593 AN: 41540

American (AMR) AF: 0.599 AC: 9165 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1987 AN: 3466

East Asian (EAS) AF: 0.706 AC: 3636 AN: 5148

South Asian (SAS) AF: 0.571 AC: 2755 AN: 4826

European-Finnish (FIN) AF: 0.798 AC: 8476 AN: 10616

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44106 AN: 67988

Other (OTH) AF: 0.539 AC: 1139 AN: 2112

Alfa AF: 0.587 Hom.: 26693

Bravo AF: 0.500

Asia WGS AF: 0.617 AC: 2145 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.49
DANN	Benign	0.88
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs910983; hg19: chr20-19738164;