chr1-38895992-C-G

Variant names:

• chr1-38895992-C-G
• NM_017821.5:c.586G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_017821.5(RHBDL2):​c.586G>C​(p.Gly196Arg) 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: RHBDL2 NM_017821.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• Publications: 0 publications found

Genes affected

RHBDL2 (HGNC:16083): (rhomboid like 2) The protein encoded by this gene is a member of the rhomboid family of integral membrane proteins. This family contains proteins that are related to Drosophila rhomboid protein. Members of this family are found in both prokaryotes and eukaryotes and are thought to function as intramembrane serine proteases. The encoded protein is thought to release soluble growth factors by proteolytic cleavage of certain membrane-bound substrates, including ephrin B2 and ephrin B3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

RRAGC-DT (HGNC:55793): (RRAGC divergent transcript)

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017821.5. 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
	RHBDL2	NM_017821.5	MANE Select	c.586G>C	p.Gly196Arg	missense	Exon 5 of 8	NP_060291.2	Q9NX52-1
	RHBDL2	NM_001304746.2		c.826G>C	p.Gly276Arg	missense	Exon 5 of 8	NP_001291675.1	B7Z1Y9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDL2	ENST00000372990.6	TSL:5 MANE Select	c.586G>C	p.Gly196Arg	missense	Exon 5 of 8	ENSP00000362081.1	Q9NX52-1
	RHBDL2	ENST00000289248.6	TSL:2	c.586G>C	p.Gly196Arg	missense	Exon 5 of 8	ENSP00000289248.2	Q9NX52-1
	RHBDL2	ENST00000863984.1		c.586G>C	p.Gly196Arg	missense	Exon 5 of 8	ENSP00000534043.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.075	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.51
MPC		0.42
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.77
gMVP		0.96
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-39361664;