rs17348572

Variant names:

• chr3-140459539-T-C
• rs17348572
• NM_022131.3:c.992T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 19 publications found

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]

ENSG00000249290 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CLSTN2	NM_022131.3	c.992T>C	p.Ile331Thr	missense_variant	Exon 7 of 17	ENST00000458420.7	NP_071414.2
CLSTN2	XM_017007022.3	c.917T>C	p.Ile306Thr	missense_variant	Exon 7 of 17		XP_016862511.1
LOC105374132	XR_007096117.1	n.49-4786A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLSTN2	ENST00000458420.7	c.992T>C	p.Ile331Thr	missense_variant	Exon 7 of 17	1	NM_022131.3	ENSP00000402460.2
CLSTN2	ENST00000511524.1	n.1180T>C		non_coding_transcript_exon_variant	Exon 7 of 11	2
ENSG00000249290	ENST00000503357.1	n.100+713A>G		intron_variant	Intron 1 of 3	3

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

GnomAD2 exomes AF: 0.0414 AC: 10382 AN: 250710 AF XY: 0.0425

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 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

African (AFR) AF: 0.0200 AC: 668 AN: 33478

American (AMR) AF: 0.0212 AC: 950 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0359 AC: 937 AN: 26134

East Asian (EAS) AF: 0.0270 AC: 1072 AN: 39696

South Asian (SAS) AF: 0.0367 AC: 3161 AN: 86248

European-Finnish (FIN) AF: 0.0562 AC: 3003 AN: 53410

Middle Eastern (MID) AF: 0.0322 AC: 186 AN: 5768

European-Non Finnish (NFE) AF: 0.0550 AC: 61097 AN: 1111862

Other (OTH) AF: 0.0441 AC: 2665 AN: 60392

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

African (AFR) AF: 0.0210 AC: 873 AN: 41552

American (AMR) AF: 0.0299 AC: 457 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3470

East Asian (EAS) AF: 0.0267 AC: 138 AN: 5170

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4822

European-Finnish (FIN) AF: 0.0545 AC: 579 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0538 AC: 3656 AN: 68012

Other (OTH) AF: 0.0398 AC: 84 AN: 2110

Alfa AF: 0.0481 Hom.: 880

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
PhyloP100		1.6
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
Mutation Taster		=82/18	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17348572; hg19: chr3-140178381; COSMIC: COSV71719239; COSMIC: COSV71719239;