Genetic Variant NM_019062.2:c.445C>G (chr1-19814657-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019062.2(RNF186):c.445C>G(p.His149Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H149N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RNF186
NM_019062.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

0 publications found

Variant links:

Genes affected

RNF186 (HGNC:25978): (ring finger protein 186) Enables ubiquitin-protein transferase activity. Involved in several processes, including intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein ubiquitination. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF186 links:

RNF186-AS1 (HGNC:41127): (RNF186 antisense RNA 1)

RNF186-AS1 links:

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ACMG classification

Classification was made for transcript

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=0.10357979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF186	NM_019062.2 link	c.445C>G	p.His149Asp	missense_variant	Exon 1 of 1	ENST00000375121.4	NP_061935.1	Q9NXI6
RNF186-AS1	NR_186008.1 link	n.145+104G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF186	ENST00000375121.4 link	c.445C>G	p.His149Asp	missense_variant	Exon 1 of 1	6	NM_019062.2	ENSP00000364263.2		Q9NXI6
RNF186-AS1	ENST00000454736.2 link	n.200+104G>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251434

AF XY:

0.00000736

show subpopulations

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.015

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.34

M_CAP

Benign

0.028

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

1.1

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.11

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0090

Polyphen

0.066

Vest4

0.19

MutPred

0.35

Gain of helix (P = 0.0325);

MVP

0.29

MPC

0.26

ClinPred

0.33

GERP RS

1.3

Varity_R

0.18

gMVP

0.54

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over