NM_018993.4:c.-36-2939_-36-2935delTTTTT

Variant names:

• chr20-19886612-CTTTTT-C
• rs11362637
• NM_018993.4:c.-36-2939_-36-2935delTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018993.4(RIN2):​c.-36-2939_-36-2935delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 517,238 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0043 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.00453) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

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.-36-2939_-36-2935delTTTTT		intron	N/A	NP_061866.1	Q8WYP3-1
	RIN2	NM_001378238.1		c.-581-2939_-581-2935delTTTTT		intron	N/A	NP_001365167.1
	RIN2	NM_001242581.2		c.-57_-53delTTTTT		upstream_gene	N/A	NP_001229510.1	Q8WYP3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.-36-2939_-36-2935delTTTTT		intron	N/A	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000648440.1		c.-190_-186delTTTTT		5_prime_UTR	Exon 1 of 12	ENSP00000498085.1	Q8WYP3-1
	RIN2	ENST00000944201.1		c.-190_-186delTTTTT		5_prime_UTR	Exon 1 of 10	ENSP00000614260.1

Frequencies

GnomAD3 genomes AF: 0.0000173 AC: 2 AN: 115278 Hom.: 0 Cov.: 0

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: 0.000428

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00430 AC: 1729 AN: 401960 Hom.: 0 AF XY: 0.00417 AC XY: 905 AN XY: 217208

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

African (AFR) AF: 0.00317 AC: 27 AN: 8504

American (AMR) AF: 0.00545 AC: 88 AN: 16146

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 45 AN: 12878

East Asian (EAS) AF: 0.00393 AC: 95 AN: 24162

South Asian (SAS) AF: 0.00413 AC: 165 AN: 39904

European-Finnish (FIN) AF: 0.00374 AC: 122 AN: 32594

Middle Eastern (MID) AF: 0.00347 AC: 8 AN: 2308

European-Non Finnish (NFE) AF: 0.00450 AC: 1098 AN: 244192

Other (OTH) AF: 0.00381 AC: 81 AN: 21272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000173 AC: 2 AN: 115278 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 54192

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

African (AFR) AF: 0.00 AC: 0 AN: 29384

American (AMR) AF: 0.00 AC: 0 AN: 10898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3012

East Asian (EAS) AF: 0.00 AC: 0 AN: 4074

South Asian (SAS) AF: 0.00 AC: 0 AN: 3414

European-Finnish (FIN) AF: 0.000428 AC: 2 AN: 4676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57268

Other (OTH) AF: 0.00 AC: 0 AN: 1532

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 309

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.040

Splicing

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

Other links and lift over

dbSNP: rs11362637; hg19: chr20-19867256;