chr1-178833512-T-C

Variant names:

• chr1-178833512-T-C
• rs140883827
• NM_152663.5:c.569T>C

Variant summary

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

The NM_152663.5(RALGPS2):​c.569T>C​(p.Ile190Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,533,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000094 (0 hom.)
• Consequence: RALGPS2 NM_152663.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.56
• Publications: 0 publications found

Genes affected

RALGPS2 (HGNC:30279): (Ral GEF with PH domain and SH3 binding motif 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of Ral protein signal transduction; regulation of catalytic activity; and small GTPase mediated signal transduction. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152663.5. 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
	RALGPS2	NM_152663.5	MANE Select	c.569T>C	p.Ile190Thr	missense	Exon 8 of 20	NP_689876.2
	RALGPS2	NM_001286247.2		c.569T>C	p.Ile190Thr	missense	Exon 8 of 19	NP_001273176.1	Q86X27-3
	RALGPS2	NM_001400042.1		c.569T>C	p.Ile190Thr	missense	Exon 8 of 19	NP_001386971.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RALGPS2	ENST00000367635.8	TSL:1 MANE Select	c.569T>C	p.Ile190Thr	missense	Exon 8 of 20	ENSP00000356607.3	Q86X27-1
	RALGPS2	ENST00000853433.1		c.569T>C	p.Ile190Thr	missense	Exon 8 of 20	ENSP00000523492.1
	RALGPS2	ENST00000853430.1		c.563T>C	p.Ile188Thr	missense	Exon 8 of 20	ENSP00000523489.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152116 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000169 AC: 3 AN: 177778 AF XY: 0.0000204

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: 0.0000334

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000941 AC: 13 AN: 1380940 Hom.: 0 Cov.: 30 AF XY: 0.00000583 AC XY: 4 AN XY: 685560

African (AFR) AF: 0.00 AC: 0 AN: 27642

American (AMR) AF: 0.00 AC: 0 AN: 24770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23906

East Asian (EAS) AF: 0.00 AC: 0 AN: 33288

South Asian (SAS) AF: 0.00 AC: 0 AN: 71964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1084090

Other (OTH) AF: 0.00 AC: 0 AN: 56970

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

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	0.59
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.34
Sift	Benign	0.047	D
Sift4G	Benign	0.062	T
Polyphen		0.45	B
Vest4		0.82
MVP		0.22
MPC		0.80
ClinPred		0.84	D
GERP RS		6.0
Varity_R		0.48
gMVP		0.74
Mutation Taster		=20/80	disease causing

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: rs140883827; hg19: chr1-178802647;