chr3-140404739-G-C

Variant names:

• chr3-140404739-G-C
• rs759504921
• NM_022131.3:c.610G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022131.3(CLSTN2):​c.610G>C​(p.Asp204His) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CLSTN2 NM_022131.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLSTN2	NM_022131.3	c.610G>C	p.Asp204His	missense_variant	Exon 4 of 17	ENST00000458420.7	NP_071414.2
CLSTN2	XM_017007022.3	c.535G>C	p.Asp179His	missense_variant	Exon 4 of 17		XP_016862511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLSTN2	ENST00000458420.7	c.610G>C	p.Asp204His	missense_variant	Exon 4 of 17	1	NM_022131.3	ENSP00000402460.2
CLSTN2	ENST00000511524.1	n.798G>C		non_coding_transcript_exon_variant	Exon 4 of 11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251258 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135792

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: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.610G>C (p.D204H) alteration is located in exon 4 (coding exon 4) of the CLSTN2 gene. This alteration results from a G to C substitution at nucleotide position 610, causing the aspartic acid (D) at amino acid position 204 to be replaced by a histidine (H). 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	-0.16	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.97	D
Vest4		0.50
MutPred		0.46		Gain of glycosylation at T203 (P = 0.1037);
MVP		0.81
MPC		0.48
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.76
gMVP		0.51

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: rs759504921; hg19: chr3-140123581; COSMIC: COSV101515391;