1-185091737-T-G

Variant names:

• chr1-185091737-T-G
• rs1651768254
• NM_007212.4:c.246T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_007212.4(RNF2):​c.246T>G​(p.Ser82Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RNF2 NM_007212.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004431
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.773

Genes affected

RNF2 (HGNC:10061): (ring finger protein 2) Polycomb group (PcG) of proteins form the multiprotein complexes that are important for the transcription repression of various genes involved in development and cell proliferation. The protein encoded by this gene is one of the PcG proteins. It has been shown to interact with, and suppress the activity of, transcription factor CP2 (TFCP2/CP2). Studies of the mouse counterpart suggested the involvement of this gene in the specification of anterior-posterior axis, as well as in cell proliferation in early development. This protein was also found to interact with huntingtin interacting protein 2 (HIP2), an ubiquitin-conjugating enzyme, and possess ubiquitin ligase activity. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.5248 (below the threshold of 3.09). Trascript score misZ: 2.9616 (below the threshold of 3.09). GenCC associations: The gene is linked to Luo-Schoch-Yamamoto syndrome.
• PP5: Variant 1-185091737-T-G is Pathogenic according to our data. Variant chr1-185091737-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 1189036.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF2	NM_007212.4	c.246T>G	p.Ser82Arg	missense_variant, splice_region_variant	Exon 3 of 7	ENST00000367510.8	NP_009143.1
RNF2	XM_011509851.4	c.246T>G	p.Ser82Arg	missense_variant, splice_region_variant	Exon 3 of 7		XP_011508153.1
RNF2	XM_011509852.3	c.246T>G	p.Ser82Arg	missense_variant, splice_region_variant	Exon 3 of 7		XP_011508154.1
RNF2	XM_005245413.4	c.99T>G	p.Ser33Arg	missense_variant, splice_region_variant	Exon 2 of 6		XP_005245470.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF2	ENST00000367510.8	c.246T>G	p.Ser82Arg	missense_variant, splice_region_variant	Exon 3 of 7	1	NM_007212.4	ENSP00000356480.3
RNF2	ENST00000367509.8	c.246T>G	p.Ser82Arg	missense_variant, splice_region_variant	Exon 3 of 6	2		ENSP00000356479.4
RNF2	ENST00000453650.2	c.246T>G	p.Ser82Arg	missense_variant, splice_region_variant	Exon 3 of 5	5		ENSP00000400722.2
RNF2	ENST00000498201.1	n.362T>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Luo-Schoch-Yamamoto syndrome Pathogenic:1

Aug 19, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.96	L;L;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.037	D;T;T
Sift4G	Benign	0.27	T;D;T
Polyphen		1.0	D;.;.
Vest4		0.71
MutPred		0.46		Gain of MoRF binding (P = 0.0302);Gain of MoRF binding (P = 0.0302);Gain of MoRF binding (P = 0.0302);
MVP		0.91
MPC		1.0
ClinPred		0.91	D
GERP RS		2.6
Varity_R		0.75
gMVP		0.92
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.20
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1651768254; hg19: chr1-185060869;