3-140459568-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022131.3(CLSTN2):c.1021A>G(p.Thr341Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,613,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

CLSTN2
NM_022131.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.770

Variant links:

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]

CLSTN2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0091020465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CLSTN2	NM_022131.3 linkuse as main transcript	c.1021A>G	p.Thr341Ala	missense_variant	7/17	ENST00000458420.7
LOC105374132	XR_007096117.1 linkuse as main transcript	n.49-4815T>C		intron_variant, non_coding_transcript_variant
CLSTN2	XM_017007022.3 linkuse as main transcript	c.946A>G	p.Thr316Ala	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CLSTN2	ENST00000458420.7 linkuse as main transcript	c.1021A>G	p.Thr341Ala	missense_variant	7/17	1	NM_022131.3	P1
	ENST00000503357.1 linkuse as main transcript	n.100+684T>C		intron_variant, non_coding_transcript_variant		3
CLSTN2	ENST00000511524.1 linkuse as main transcript	n.1209A>G		non_coding_transcript_exon_variant	7/11	2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00576

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:

0.000479

GnomAD3 exomes

AF:

0.000243

AC:

AN:

250982

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000135

AC:

197

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00562

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000138

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000257

Hom.:

Bravo

AF:

0.000151

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.1021A>G (p.T341A) alteration is located in exon 7 (coding exon 7) of the CLSTN2 gene. This alteration results from a A to G substitution at nucleotide position 1021, causing the threonine (T) at amino acid position 341 to be replaced by an alanine (A). 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

0.058

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Benign

0.62

DEOGEN2

Benign

0.11

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.79

M_CAP

Benign

0.0097

MetaRNN

Benign

0.0091

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.49

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.41

REVEL

Benign

0.026

Sift

Benign

0.89

Sift4G

Benign

1.0

Polyphen

0.0050

Vest4

0.12

MutPred

0.37

Gain of sheet (P = 0.0125);

MVP

0.35

MPC

0.17

ClinPred

0.022

GERP RS

1.6

Varity_R

0.043

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over