chr20-19975450-C-A

Position:

• chr20-19975450-C-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018993.4(RIN2):​c.1425C>A​(p.Pro475=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,614,044 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (34 hom.)
• Consequence: RIN2 NM_018993.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0300

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 20-19975450-C-A is Benign according to our data. Variant chr20-19975450-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 212053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00394 (600/152334) while in subpopulation AMR AF= 0.00843 (129/15296). AF 95% confidence interval is 0.00725. There are 4 homozygotes in gnomad4. There are 301 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIN2	NM_018993.4	c.1425C>A	p.Pro475=	synonymous_variant	9/13	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.1425C>A	p.Pro475=	synonymous_variant	9/13	2	NM_018993.4	ENSP00000255006	P1
RIN2	ENST00000440354.2	c.464-14556C>A		intron_variant		1		ENSP00000391239
RIN2	ENST00000484638.1	n.1269C>A		non_coding_transcript_exon_variant	5/9	1
RIN2	ENST00000648440.1	c.1425C>A	p.Pro475=	synonymous_variant	8/12			ENSP00000498085	P1

Frequencies

GnomAD3 genomes AF: 0.00393 AC: 598 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00522

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00392 AC: 978 AN: 249176 Hom.: 7 AF XY: 0.00417 AC XY: 564 AN XY: 135196

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00676

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00255

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00573

Gnomad OTH exome AF: 0.00628

GnomAD4 exome AF: 0.00517 AC: 7561 AN: 1461710 Hom.: 34 Cov.: 36 AF XY: 0.00520 AC XY: 3781 AN XY: 727136

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00758

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00275

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00585

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00394 AC: 600 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00404 AC XY: 301 AN XY: 74486

Gnomad4 AFR AF: 0.00139

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00522

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00392 Hom.: 6

Bravo AF: 0.00431

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RIN2: BP4, BP7, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 26, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.4
DANN	Benign	0.88

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: rs188147644; hg19: chr20-19956094; COSMIC: COSV99658167; COSMIC: COSV99658167;