chr6-33198322-C-G

Variant names:

• chr6-33198322-C-G
• NM_021976.5:c.626G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021976.5(RXRB):​c.626G>C​(p.Gly209Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53
• Publications: 0 publications found

Genes affected

RXRB (HGNC:10478): (retinoid X receptor beta) This gene encodes a member of the retinoid X receptor (RXR) family of nuclear receptors which are involved in mediating the effects of retinoic acid (RA). The encoded protein forms homodimers with the retinoic acid, thyroid hormone, and vitamin D receptors, increasing both DNA binding and transcriptional function on their respective response elements. This gene lies within the major histocompatibility complex (MHC) class II region on chromosome 6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021976.5. 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
	RXRB	NM_021976.5	MANE Select	c.626G>C	p.Gly209Ala	missense	Exon 3 of 10	NP_068811.1	Q5STP9
	RXRB	NM_001270401.2		c.626G>C	p.Gly209Ala	missense	Exon 3 of 10	NP_001257330.1	A0A0S2Z570
	RXRB	NM_001291989.2		c.56G>C	p.Gly19Ala	missense	Exon 2 of 9	NP_001278918.1	A0A0G2JKR7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRB	ENST00000374680.4	TSL:1 MANE Select	c.626G>C	p.Gly209Ala	missense	Exon 3 of 10	ENSP00000363812.3	P28702-1
	RXRB	ENST00000374685.8	TSL:1	c.626G>C	p.Gly209Ala	missense	Exon 3 of 10	ENSP00000363817.4	P28702-3
	RXRB	ENST00000865272.1		c.626G>C	p.Gly209Ala	missense	Exon 3 of 10	ENSP00000535331.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.93		Loss of disorder (P = 0.0909)
MVP		0.96
MPC		3.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.58
gMVP		0.87
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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

hg19: chr6-33166099;