rs17348572

Positions:

• chr3-140459539-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022131.3(CLSTN2):​c.992T>C​(p.Ile331Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0494 in 1,613,962 control chromosomes in the GnomAD database, including 2,107 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.040 (146 hom., cov: 32)
  • Exomes 𝑓: 0.050 (1961 hom.)
• Consequence: CLSTN2 NM_022131.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021517873).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLSTN2	NM_022131.3	c.992T>C	p.Ile331Thr	missense_variant	7/17	ENST00000458420.7
LOC105374132	XR_007096117.1	n.49-4786A>G		intron_variant, non_coding_transcript_variant
CLSTN2	XM_017007022.3	c.917T>C	p.Ile306Thr	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLSTN2	ENST00000458420.7	c.992T>C	p.Ile331Thr	missense_variant	7/17	1	NM_022131.3	P1
	ENST00000503357.1	n.100+713A>G		intron_variant, non_coding_transcript_variant		3
CLSTN2	ENST00000511524.1	n.1180T>C		non_coding_transcript_exon_variant	7/11	2

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6063 AN: 152132 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.0350

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0414 AC: 10382 AN: 250710 Hom.: 236 AF XY: 0.0425 AC XY: 5761 AN XY: 135466

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.0252

Gnomad SAS exome AF: 0.0360

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0397

GnomAD4 exome AF: 0.0504 AC: 73739 AN: 1461712 Hom.: 1961 Cov.: 32 AF XY: 0.0503 AC XY: 36547 AN XY: 727150

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0359

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.0367

Gnomad4 FIN exome AF: 0.0562

Gnomad4 NFE exome AF: 0.0550

Gnomad4 OTH exome AF: 0.0441

GnomAD4 genome AF: 0.0398 AC: 6064 AN: 152250 Hom.: 146 Cov.: 32 AF XY: 0.0399 AC XY: 2972 AN XY: 74436

Gnomad4 AFR AF: 0.0210

Gnomad4 AMR AF: 0.0299

Gnomad4 ASJ AF: 0.0300

Gnomad4 EAS AF: 0.0267

Gnomad4 SAS AF: 0.0346

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.0538

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0489 Hom.: 503

Bravo AF: 0.0367

TwinsUK AF: 0.0515 AC: 191

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0524 AC: 451

ExAC AF: 0.0416 AC: 5054

Asia WGS AF: 0.0380 AC: 133 AN: 3478

EpiCase AF: 0.0499

EpiControl AF: 0.0510

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.91	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.045
Sift	Benign	0.23	T
Sift4G	Benign	0.49	T
Polyphen		0.010	B
Vest4		0.12
MPC		0.23
ClinPred		0.0093	T
GERP RS		5.4
Varity_R		0.20
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs17348572; hg19: chr3-140178381; COSMIC: COSV71719239; COSMIC: COSV71719239;