20-19886731-G-T

Variant names:

• chr20-19886731-G-T
• rs770609415
• NM_018993.4:c.-36-2835G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018993.4(RIN2):​c.-36-2835G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000259 in 1,546,604 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RIN2 NM_018993.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0260
• Publications: 0 publications found

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]

RIN2 Gene-Disease associations (from GenCC):

• RIN2 syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09877893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIN2	NM_018993.4	c.-36-2835G>T		intron_variant	Intron 2 of 12	ENST00000255006.12	NP_061866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIN2	ENST00000255006.12	c.-36-2835G>T		intron_variant	Intron 2 of 12	2	NM_018993.4	ENSP00000255006.7
RIN2	ENST00000648440.1	c.-86G>T		5_prime_UTR_variant	Exon 1 of 12			ENSP00000498085.1
RIN2	ENST00000432334.2	n.537-2835G>T		intron_variant	Intron 3 of 3	4
RIN2	ENST00000648165.1	n.618-2835G>T		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00000668 AC: 1 AN: 149720 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000669 AC: 1 AN: 149458 AF XY: 0.0000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1396884 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 688992

African (AFR) AF: 0.00 AC: 0 AN: 31386

American (AMR) AF: 0.00 AC: 0 AN: 35312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 35716

South Asian (SAS) AF: 0.00 AC: 0 AN: 78892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078324

Other (OTH) AF: 0.0000172 AC: 1 AN: 58076

GnomAD4 genome AF: 0.00000668 AC: 1 AN: 149720 Hom.: 0 Cov.: 29 AF XY: 0.0000137 AC XY: 1 AN XY: 72886

African (AFR) AF: 0.00 AC: 0 AN: 40436

American (AMR) AF: 0.00 AC: 0 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00 AC: 0 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67804

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62G>T (p.S21I) alteration is located in exon 1 (coding exon 1) of the RIN2 gene. This alteration results from a G to T substitution at nucleotide position 62, causing the serine (S) at amino acid position 21 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.97
DANN	Benign	0.89
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.026
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.028
Sift	Uncertain	0.018	D
Vest4		0.17
MutPred		0.32		Loss of disorder (P = 2e-04);
MVP		0.23
MPC		0.23
ClinPred		0.53	D
GERP RS		-0.11
PromoterAI		-0.062	Neutral
gMVP		0.068

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770609415; hg19: chr20-19867375;