rs200780805

Variant names:

• chr20-19975029-C-G
• rs200780805
• NM_018993.4:c.1004C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-19975029-C-G
• chr20-19975029-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018993.4(RIN2):​c.1004C>G​(p.Pro335Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,613,490 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: RIN2 NM_018993.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 7.58
• Publications: 7 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010970145).
• BP6: Variant 20-19975029-C-G is Benign according to our data. Variant chr20-19975029-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436539.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000966 (147/152230) while in subpopulation AMR AF = 0.00235 (36/15302). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.1004C>G	p.Pro335Arg	missense	Exon 9 of 13	NP_061866.1	Q8WYP3-1
	RIN2	NM_001242581.2		c.1151C>G	p.Pro384Arg	missense	Exon 8 of 12	NP_001229510.1	Q8WYP3-2
	RIN2	NM_001378238.1		c.386C>G	p.Pro129Arg	missense	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.1004C>G	p.Pro335Arg	missense	Exon 9 of 13	ENSP00000255006.7	Q8WYP3-1
	RIN2	ENST00000440354.2	TSL:1	c.463+14218C>G		intron	N/A	ENSP00000391239.2	E7EPJ1
	RIN2	ENST00000484638.1	TSL:1	n.848C>G		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000937 AC: 232 AN: 247546 AF XY: 0.000920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00116 AC: 1691 AN: 1461260 Hom.: 3 Cov.: 38 AF XY: 0.00113 AC XY: 821 AN XY: 726888

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.00273 AC: 122 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.000132 AC: 7 AN: 52958

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00133 AC: 1480 AN: 1111866

Other (OTH) AF: 0.00128 AC: 77 AN: 60370

GnomAD4 genome AF: 0.000966 AC: 147 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74424

African (AFR) AF: 0.000144 AC: 6 AN: 41546

American (AMR) AF: 0.00235 AC: 36 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68004

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00107 Hom.: 1

Bravo AF: 0.00117

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00131 AC: 11

ExAC AF: 0.000885 AC: 107

EpiCase AF: 0.00109

EpiControl AF: 0.00166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	1	RIN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.55
MVP		0.56
MPC		0.73
ClinPred		0.13	T
GERP RS		5.6
Varity_R		0.40
gMVP		0.38
Mutation Taster		=29/71	disease causing

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: rs200780805; hg19: chr20-19955673; COSMIC: COSV99656923; COSMIC: COSV99656923;