3-140403621-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022131.3(CLSTN2):c.233-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,600,578 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (50 hom.)
• Consequence: CLSTN2 NM_022131.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005154
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.919

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-140403621-T-G is Benign according to our data. Variant chr3-140403621-T-G is described in ClinVar as [Benign]. Clinvar id is 782435.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2075/152352) while in subpopulation AFR AF= 0.0463 (1925/41582). AF 95% confidence interval is 0.0446. There are 37 homozygotes in gnomad4. There are 1017 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLSTN2	NM_022131.3	c.233-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000458420.7
CLSTN2	XM_017007022.3	c.158-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLSTN2	ENST00000458420.7	c.233-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_022131.3	P1
CLSTN2	ENST00000511524.1	n.421-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2075 AN: 152234 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00370 AC: 895 AN: 242054 Hom.: 18 AF XY: 0.00264 AC XY: 345 AN XY: 130570

Gnomad AFR exome AF: 0.0459

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000702

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000228

Gnomad OTH exome AF: 0.00171

GnomAD4 exome AF: 0.00144 AC: 2092 AN: 1448226 Hom.: 50 Cov.: 31 AF XY: 0.00130 AC XY: 935 AN XY: 719088

Gnomad4 AFR exome AF: 0.0454

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000184

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.0136 AC: 2075 AN: 152352 Hom.: 37 Cov.: 32 AF XY: 0.0137 AC XY: 1017 AN XY: 74504

Gnomad4 AFR AF: 0.0463

Gnomad4 AMR AF: 0.00692

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00865 Hom.: 11

Bravo AF: 0.0152

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	8.0
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0052
dbscSNV1_RF	Benign	0.084
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: rs72981079; hg19: chr3-140122463;