20-19975749-AC-ACC

Variant names:

• chr20-19975749-A-AC
• rs759390822
• NM_018993.4:c.1731dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018993.4(RIN2):​c.1731dupC​(p.Ile578HisfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,610,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RIN2 NM_018993.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0610
• Publications: 1 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-19975749-A-AC is Pathogenic according to our data. Variant chr20-19975749-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 137627.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.1731dupC	p.Ile578HisfsTer7	frameshift	Exon 9 of 13	NP_061866.1	Q8WYP3-1
	RIN2	NM_001242581.2		c.1878dupC	p.Ile627HisfsTer7	frameshift	Exon 8 of 12	NP_001229510.1	Q8WYP3-2
	RIN2	NM_001378238.1		c.1113dupC	p.Ile372HisfsTer7	frameshift	Exon 8 of 12	NP_001365167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.1731dupC	p.Ile578HisfsTer7	frameshift	Exon 9 of 13	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000440354.2	TSL:1	c.464-14250dupC		intron	N/A	ENSP00000391239.2	E7EPJ1
	RIN2	ENST00000484638.1	TSL:1	n.1575dupC		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000165 AC: 4 AN: 242440 AF XY: 0.00

Gnomad AFR exome AF: 0.0000674

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000926

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460098 Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11 AN XY: 726262

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.000190 AC: 10 AN: 52750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111372

Other (OTH) AF: 0.0000166 AC: 1 AN: 60330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000154716), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150090 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73144

African (AFR) AF: 0.00 AC: 0 AN: 40574

American (AMR) AF: 0.00 AC: 0 AN: 15002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67604

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.0000489 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	RIN2 syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs759390822; hg19: chr20-19956393; COSMIC: COSV54783933; COSMIC: COSV54783933;