chr20-19886612-CTTTT-C

Variant names:

• chr20-19886612-CTTTT-C
• rs11362637
• NM_018993.4:c.-36-2938_-36-2935delTTTT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_018993.4(RIN2):​c.-36-2938_-36-2935delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 514,470 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: 0.011 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0108 (4328/399198) while in subpopulation NFE AF= 0.0115 (2800/242574). AF 95% confidence interval is 0.0112. There are 0 homozygotes in gnomad4_exome. There are 2331 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2938_-36-2935delTTTT		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.-36-2938_-36-2935delTTTT		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440	c.-189_-186delTTTT		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2938_537-2935delTTTT		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2938_618-2935delTTTT		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0000174 AC: 2 AN: 115272 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000293

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0108 AC: 4328 AN: 399198 Hom.: 0 AF XY: 0.0108 AC XY: 2331 AN XY: 215596

Gnomad4 AFR exome AF: 0.00866

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.00941

Gnomad4 EAS exome AF: 0.00994

Gnomad4 SAS exome AF: 0.0106

Gnomad4 FIN exome AF: 0.00735

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.0000174 AC: 2 AN: 115272 Hom.: 0 Cov.: 0 AF XY: 0.0000369 AC XY: 2 AN XY: 54188

Gnomad4 AFR AF: 0.0000340

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000293

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11362637; hg19: chr20-19867256;