11-22827861-G-C

Position:

• chr11-22827861-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_148893.3(SVIP):​c.68C>G​(p.Ala23Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SVIP NM_148893.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.832

Genes affected

SVIP (HGNC:25238): (small VCP interacting protein) Endoplasmic reticulum-associated degradation (ERAD) is the pathway by which misfolded proteins in the endoplasmic reticulum are targeted to the proteasome for degradation. Multiple specialized proteins interact with one another during ERAD to complete this process. The protein encoded by this gene is an inhibitor of ERAD, functioning to disrupt the interaction of these protein components. This downregulation of ERAD may be needed to protect the cell from overactive protein degradation. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

GAS2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1269618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SVIP	NM_148893.3	c.68C>G	p.Ala23Gly	missense_variant	2/4	ENST00000354193.5	NP_683691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SVIP	ENST00000354193.5	c.68C>G	p.Ala23Gly	missense_variant	2/4	1	NM_148893.3	ENSP00000346130	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

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

Apr 24, 2024

The c.68C>G (p.A23G) alteration is located in exon 2 (coding exon 2) of the SVIP gene. This alteration results from a C to G substitution at nucleotide position 68, causing the alanine (A) at amino acid position 23 to be replaced by a glycine (G). 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	0.18
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.075
Sift	Benign	0.18	T
Sift4G	Benign	0.20	T
Polyphen		0.40	B
Vest4		0.38
MutPred		0.10		Loss of stability (P = 0.0434);
MVP		0.25
MPC		0.57
ClinPred		0.95	D
GERP RS		1.1
Varity_R		0.088
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1590174527; hg19: chr11-22849407;