3-140448605-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022131.3(CLSTN2):c.874G>A(p.Val292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CLSTN2 NM_022131.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.635

Genes affected

CLSTN2 (HGNC:17448): (calsyntenin 2) Predicted to enable calcium ion binding activity. Predicted to be involved in positive regulation of synapse assembly and positive regulation of synaptic transmission. Predicted to be located in postsynaptic density. Predicted to be active in cell surface; glutamatergic synapse; and postsynaptic membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35344854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLSTN2	NM_022131.3	c.874G>A	p.Val292Met	missense_variant	6/17	ENST00000458420.7
CLSTN2	XM_017007022.3	c.799G>A	p.Val267Met	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLSTN2	ENST00000458420.7	c.874G>A	p.Val292Met	missense_variant	6/17	1	NM_022131.3	P1
CLSTN2	ENST00000511524.1	n.1062G>A		non_coding_transcript_exon_variant	6/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251162 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135712

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461826 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Sep 26, 2023

The c.874G>A (p.V292M) alteration is located in exon 6 (coding exon 6) of the CLSTN2 gene. This alteration results from a G to A substitution at nucleotide position 874, causing the valine (V) at amino acid position 292 to be replaced by a methionine (M). 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	-0.061	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.97	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.040	D
Sift4G	Benign	0.076	T
Polyphen		0.99	D
Vest4		0.41
MutPred		0.39		Loss of catalytic residue at V292 (P = 0.2154);
MVP		0.84
MPC		0.22
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.12
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs1261844629; hg19: chr3-140167447; COSMIC: COSV71724228; COSMIC: COSV71724228;