20-19886606-CTTCTTCTTTT-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.-36-2957_-36-2948del 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

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 20-19886606-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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.-36-2957_-36-2948del		intron_variant		ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2957_-36-2948del		intron_variant		2	NM_018993.4	P1
RIN2	ENST00000648440.1	c.-208_-199del		5_prime_UTR_variant	1/12			P1
RIN2	ENST00000432334.2	n.537-2957_537-2948del		intron_variant, non_coding_transcript_variant		4
RIN2	ENST00000648165.1	n.618-2957_618-2948del		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.0105

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000181

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000399

Gnomad4 OTH exome AF: 0.000710

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

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.000960

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000635

Gnomad4 OTH AF: 0.00284

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 12, 2018

- -

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: rs1342006597; hg19: chr20-19867250;