17-2375814-C-T

Variant names:

• chr17-2375814-C-T
• rs147179672
• NM_014853.3:c.2423C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014853.3(SGSM2):​c.2423C>T​(p.Pro808Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000833 in 1,559,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P808R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SGSM2 NM_014853.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.168
• Publications: 0 publications found

Genes affected

SGSM2 (HGNC:29026): (small G protein signaling modulator 2) The protein encoded by this gene is a GTPase activator with activity towards RAB32 and RAB33B, which are regulators of membrane trafficking. The encoded protein inactivates RAB32 and can bind RAB9A-GTP, a protein required for RAB32 activation. [provided by RefSeq, Oct 2016]

SGSM2-AS1 (HGNC:56091): (SGSM2 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017583728).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014853.3. 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
	SGSM2	NM_014853.3	MANE Select	c.2423C>T	p.Pro808Leu	missense	Exon 18 of 24	NP_055668.2	O43147-2
	SGSM2	NM_001098509.2		c.2288C>T	p.Pro763Leu	missense	Exon 17 of 23	NP_001091979.1	O43147-1
	SGSM2	NM_001346700.2		c.2288C>T	p.Pro763Leu	missense	Exon 17 of 23	NP_001333629.1	O43147-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSM2	ENST00000268989.8	TSL:1 MANE Select	c.2423C>T	p.Pro808Leu	missense	Exon 18 of 24	ENSP00000268989.3	O43147-2
	SGSM2	ENST00000426855.6	TSL:1	c.2288C>T	p.Pro763Leu	missense	Exon 17 of 23	ENSP00000415107.2	O43147-1
	SGSM2	ENST00000968832.1		c.2426C>T	p.Pro809Leu	missense	Exon 18 of 24	ENSP00000638891.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000336 AC: 7 AN: 208408 AF XY: 0.0000360

Gnomad AFR exome AF: 0.000381

Gnomad AMR exome AF: 0.0000339

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000497 AC: 7 AN: 1407384 Hom.: 0 Cov.: 32 AF XY: 0.00000864 AC XY: 6 AN XY: 694570

African (AFR) AF: 0.000156 AC: 5 AN: 32014

American (AMR) AF: 0.0000510 AC: 2 AN: 39232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22450

East Asian (EAS) AF: 0.00 AC: 0 AN: 39246

South Asian (SAS) AF: 0.00 AC: 0 AN: 78114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085744

Other (OTH) AF: 0.00 AC: 0 AN: 57992

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74514

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000245 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

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	Benign	0.070
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	6.0
DANN	Benign	0.63
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.17
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.0060
Sift	Benign	0.061	T
Sift4G	Benign	0.11	T
Polyphen		0.010	B
Vest4		0.12
MVP		0.17
MPC		0.13
ClinPred		0.016	T
GERP RS		-0.20
Varity_R		0.031
gMVP		0.17
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147179672; hg19: chr17-2279108;