rs35142632

chr20-19975452-C-Gchr20-19975452-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6 BS1 BS2

The NM_018993.4(RIN2):c.1427C>G(p.Pro476Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000252 in 1,614,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P476A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: RIN2 NM_018993.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.78

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004856497).
• BP6: Variant 20-19975452-C-G is Benign according to our data. Variant chr20-19975452-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212054.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00148 (225/152368) while in subpopulation AFR AF= 0.00522 (217/41592). AF 95% confidence interval is 0.00465. There are 1 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIN2	NM_018993.4	c.1427C>G	p.Pro476Arg	missense_variant	9/13	ENST00000255006.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIN2	ENST00000255006.12	c.1427C>G	p.Pro476Arg	missense_variant	9/13	2	NM_018993.4	P1
RIN2	ENST00000440354.2	c.464-14554C>G		intron_variant		1
RIN2	ENST00000484638.1	n.1271C>G		non_coding_transcript_exon_variant	5/9	1
RIN2	ENST00000648440.1	c.1427C>G	p.Pro476Arg	missense_variant	8/12			P1

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152250 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00523

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000293 AC: 73 AN: 249192 Hom.: 2 AF XY: 0.000281 AC XY: 38 AN XY: 135196

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1461710 Hom.: 0 Cov.: 36 AF XY: 0.000111 AC XY: 81 AN XY: 727136

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152368 Hom.: 1 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74512

Gnomad4 AFR AF: 0.00522

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.00156

ESP6500AA AF: 0.00354 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000356 AC: 43

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
Polyphen		1.0	D;.
Vest4		0.57
MVP		0.52
MPC		0.77
ClinPred		0.049	T
GERP RS		5.6
Varity_R		0.21
gMVP		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: rs35142632; hg19: chr20-19956096;