rs374058245

chr20-19974948-C-Achr20-19974948-C-Gchr20-19974948-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_018993.4(RIN2):c.923C>A(p.Pro308Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000985 in 1,603,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P308A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: RIN2 NM_018993.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.71

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14283267).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000205 (31/151488) while in subpopulation EAS AF= 0.00078 (4/5126). AF 95% confidence interval is 0.000355. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.923C>A	p.Pro308Gln	missense_variant	9/13	ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.923C>A	p.Pro308Gln	missense_variant	9/13	2	NM_018993.4	P1
RIN2	ENST00000440354.2	c.463+14137C>A		intron_variant		1
RIN2	ENST00000484638.1	n.767C>A		non_coding_transcript_exon_variant	5/9	1
RIN2	ENST00000648440.1	c.923C>A	p.Pro308Gln	missense_variant	8/12			P1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 151372 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000779

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000166 AC: 41 AN: 247140 Hom.: 0 AF XY: 0.000164 AC XY: 22 AN XY: 134472

Gnomad AFR exome AF: 0.000197

Gnomad AMR exome AF: 0.000498

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.000281

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000875 AC: 127 AN: 1452176 Hom.: 0 Cov.: 51 AF XY: 0.0000982 AC XY: 71 AN XY: 722778

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000707

Gnomad4 OTH exome AF: 0.000117

GnomAD4 genome AF: 0.000205 AC: 31 AN: 151488 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74116

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000780

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.000257

ExAC AF: 0.000166 AC: 20

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 23, 2015

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2021

The c.923C>A (p.P308Q) alteration is located in exon 7 (coding exon 7) of the RIN2 gene. This alteration results from a C to A substitution at nucleotide position 923, causing the proline (P) at amino acid position 308 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 18, 2022

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 308 of the RIN2 protein (p.Pro308Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 212056). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

RIN2 syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.25		Loss of glycosylation at P308 (P = 4e-04);.;
MVP		0.60
MPC		0.72
ClinPred		0.36	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.55

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: rs374058245; hg19: chr20-19955592;