20-19886612-CTTTTTTTT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018993.4(RIN2):c.-36-2942_-36-2935del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 520,924 control chromosomes in the GnomAD database, including 27 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (19 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.204

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 20-19886612-CTTTTTTTT-C is Benign according to our data. Variant chr20-19886612-CTTTTTTTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1191188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00914 (1054/115272) while in subpopulation AFR AF= 0.0343 (1009/29430). AF 95% confidence interval is 0.0325. There are 19 homozygotes in gnomad4. There are 483 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.-36-2942_-36-2935del		intron_variant		ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2942_-36-2935del		intron_variant		2	NM_018993.4	P1
RIN2	ENST00000648440.1	c.-193_-186del		5_prime_UTR_variant	1/12			P1
RIN2	ENST00000432334.2	n.537-2942_537-2935del		intron_variant, non_coding_transcript_variant		4
RIN2	ENST00000648165.1	n.618-2942_618-2935del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00907 AC: 1046 AN: 115284 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.0341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000332

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000873

Gnomad OTH AF: 0.00587

GnomAD4 exome AF: 0.00121 AC: 490 AN: 405652 Hom.: 8 AF XY: 0.00101 AC XY: 221 AN XY: 219186

Gnomad4 AFR exome AF: 0.0431

Gnomad4 AMR exome AF: 0.00196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.0000305

Gnomad4 NFE exome AF: 0.0000974

Gnomad4 OTH exome AF: 0.00251

GnomAD4 genome AF: 0.00914 AC: 1054 AN: 115272 Hom.: 19 Cov.: 0 AF XY: 0.00891 AC XY: 483 AN XY: 54210

Gnomad4 AFR AF: 0.0343

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.000332

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000873

Gnomad4 OTH AF: 0.00584

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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;