20-19886612-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018993.4(RIN2):c.-36-2954C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 16)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.852

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-19886612-C-T is Benign according to our data. Variant chr20-19886612-C-T is described in ClinVar as [Benign]. Clinvar id is 1228223.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.-36-2954C>T		intron_variant		ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2954C>T		intron_variant		2	NM_018993.4	P1
RIN2	ENST00000648440.1	c.-205C>T		5_prime_UTR_variant	1/12			P1
RIN2	ENST00000432334.2	n.537-2954C>T		intron_variant, non_coding_transcript_variant		4
RIN2	ENST00000648165.1	n.618-2954C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 1731 AN: 115190 Hom.: 61 Cov.: 16

Gnomad AFR AF: 0.0557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00541

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: 0.000279

Gnomad OTH AF: 0.0150

GnomAD4 exome AF: 0.000382 AC: 155 AN: 405554 Hom.: 0 Cov.: 6 AF XY: 0.000374 AC XY: 82 AN XY: 219132

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.000918

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000821

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000122

Gnomad4 NFE exome AF: 0.0000852

Gnomad4 OTH exome AF: 0.000605

GnomAD4 genome AF: 0.0150 AC: 1732 AN: 115178 Hom.: 62 Cov.: 16 AF XY: 0.0147 AC XY: 796 AN XY: 54180

Gnomad4 AFR AF: 0.0557

Gnomad4 AMR AF: 0.00532

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000295

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0149

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.53
Dann	Benign	0.44

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: rs6112633; hg19: chr20-19867256; COSMIC: COSV54788751; COSMIC: COSV54788751;