rs548499908

Variant names:

• chr20-19975183-G-A
• rs548499908
• NM_018993.4:c.1158G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-19975183-G-A
• chr20-19975183-G-C
• chr20-19975183-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_018993.4(RIN2):​c.1158G>A​(p.Pro386Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,606,928 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P386P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: RIN2 NM_018993.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.140
• 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, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-19975183-G-A is Benign according to our data. Variant chr20-19975183-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2896442.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.14 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018993.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	NM_018993.4	MANE Select	c.1158G>A	p.Pro386Pro	synonymous	Exon 9 of 13	NP_061866.1	Q8WYP3-1
	RIN2	NM_001242581.2		c.1305G>A	p.Pro435Pro	synonymous	Exon 8 of 12	NP_001229510.1	Q8WYP3-2
	RIN2	NM_001378238.1		c.540G>A	p.Pro180Pro	synonymous	Exon 8 of 12	NP_001365167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIN2	ENST00000255006.12	TSL:2 MANE Select	c.1158G>A	p.Pro386Pro	synonymous	Exon 9 of 13	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000440354.2	TSL:1	c.463+14372G>A		intron	N/A	ENSP00000391239.2	E7EPJ1
	RIN2	ENST00000484638.1	TSL:1	n.1002G>A		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1454714 Hom.: 0 Cov.: 36 AF XY: 0.00000691 AC XY: 5 AN XY: 723204

African (AFR) AF: 0.0000300 AC: 1 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 43724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109084

Other (OTH) AF: 0.0000166 AC: 1 AN: 60162

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.78
PhyloP100		-0.14

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

Other links and lift over

dbSNP: rs548499908; hg19: chr20-19955827;