chr16-88698563-T-C

Variant names:

• chr16-88698563-T-C
• rs1202106467
• NM_178841.4:c.587A>G

Variant summary

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

The NM_178841.4(RNF166):​c.587A>G​(p.Lys196Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000764 in 1,569,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: RNF166 NM_178841.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71
• Publications: 1 publications found

Genes affected

RNF166 (HGNC:28856): (ring finger protein 166) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein polyubiquitination and ubiquitin-dependent protein catabolic process. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259813 (HGNC:):

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=0.12015998).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF166	NM_178841.4	c.587A>G	p.Lys196Arg	missense_variant	Exon 5 of 6	ENST00000312838.9	NP_849163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF166	ENST00000312838.9	c.587A>G	p.Lys196Arg	missense_variant	Exon 5 of 6	1	NM_178841.4	ENSP00000326095.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000705 AC: 10 AN: 1417788 Hom.: 0 Cov.: 31 AF XY: 0.00000998 AC XY: 7 AN XY: 701262

African (AFR) AF: 0.00 AC: 0 AN: 32256

American (AMR) AF: 0.00 AC: 0 AN: 38938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25136

East Asian (EAS) AF: 0.00 AC: 0 AN: 37028

South Asian (SAS) AF: 0.00 AC: 0 AN: 80476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00000918 AC: 10 AN: 1089408

Other (OTH) AF: 0.00 AC: 0 AN: 58740

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.587A>G (p.K196R) alteration is located in exon 5 (coding exon 5) of the RNF166 gene. This alteration results from a A to G substitution at nucleotide position 587, causing the lysine (K) at amino acid position 196 to be replaced by an arginine (R). 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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T;.;.;.;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T;.;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.33	N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0060	B;.;.;.;.
Vest4		0.39
MutPred		0.40		Loss of ubiquitination at K196 (P = 0.0103);.;.;.;.;
MVP		0.34
MPC		0.21
ClinPred		0.98	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.46
Mutation Taster		=83/17	polymorphism

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: rs1202106467; hg19: chr16-88764971;