17-2376209-T-C

Position:

• chr17-2376209-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014853.3(SGSM2):​c.2557T>C​(p.Tyr853His) variant causes a missense change involving the alteration of a conserved nucleotide. 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: SGSM2 NM_014853.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSM2	NM_014853.3	c.2557T>C	p.Tyr853His	missense_variant	19/24	ENST00000268989.8	NP_055668.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSM2	ENST00000268989.8	c.2557T>C	p.Tyr853His	missense_variant	19/24	1	NM_014853.3	ENSP00000268989	P4
SGSM2	ENST00000426855.6	c.2422T>C	p.Tyr808His	missense_variant	18/23	1		ENSP00000415107	A1
SGSM2-AS1	ENST00000574290.1	n.401+404A>G		intron_variant, non_coding_transcript_variant		5
SGSM2	ENST00000574563.5	c.2422T>C	p.Tyr808His	missense_variant	18/23	2		ENSP00000459126

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2022

The c.2557T>C (p.Y853H) alteration is located in exon 19 (coding exon 19) of the SGSM2 gene. This alteration results from a T to C substitution at nucleotide position 2557, causing the tyrosine (Y) at amino acid position 853 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.58	.;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Uncertain	0.31
Sift	Benign	0.047	D;D;.
Sift4G	Uncertain	0.048	D;T;D
Polyphen		0.96	D;D;P
Vest4		0.81
MutPred		0.54		.;Gain of catalytic residue at R806 (P = 0.1283);Gain of catalytic residue at R806 (P = 0.1283);
MVP		0.42
MPC		0.29
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.69

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-2279503;