chr20-19886606-CTTCTTCTTTT-C

Variant names:

• chr20-19886606-CTTCTTCTTTT-C
• rs1342006597
• NM_018993.4:c.-36-2957_-36-2948delCTTCTTTTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018993.4(RIN2):​c.-36-2957_-36-2948delCTTCTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 829,376 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.33
• 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 -10 ACMG points.

• BP6: Variant 20-19886606-CTTCTTCTTTT-C is Benign according to our data. Variant chr20-19886606-CTTCTTCTTTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1215702.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00395 (504/127716) while in subpopulation AFR AF = 0.0151 (484/32114). AF 95% confidence interval is 0.014. There are 3 homozygotes in GnomAd4. There are 240 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2957_-36-2948delCTTCTTTTTT		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.-36-2957_-36-2948delCTTCTTTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-208_-199delCTTCTTTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2957_537-2948delCTTCTTTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2957_618-2948delCTTCTTTTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00393 AC: 502 AN: 127660 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000960

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: 0.0000635

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000295 AC: 207 AN: 701660 Hom.: 0 AF XY: 0.000278 AC XY: 102 AN XY: 367210

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

African (AFR) AF: 0.0105 AC: 154 AN: 14600

American (AMR) AF: 0.000381 AC: 9 AN: 23594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18940

East Asian (EAS) AF: 0.00 AC: 0 AN: 30784

South Asian (SAS) AF: 0.0000181 AC: 1 AN: 55138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.0000399 AC: 19 AN: 476408

Other (OTH) AF: 0.000710 AC: 24 AN: 33798

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00395 AC: 504 AN: 127716 Hom.: 3 Cov.: 0 AF XY: 0.00394 AC XY: 240 AN XY: 60862

African (AFR) AF: 0.0151 AC: 484 AN: 32114

American (AMR) AF: 0.000960 AC: 11 AN: 11462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3316

East Asian (EAS) AF: 0.00 AC: 0 AN: 4136

South Asian (SAS) AF: 0.00 AC: 0 AN: 3602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.0000635 AC: 4 AN: 63022

Other (OTH) AF: 0.00284 AC: 5 AN: 1758

Alfa AF: 0.00287 Hom.: 0

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1342006597; hg19: chr20-19867250;