12-7135836-A-G

Variant names:

• chr12-7135836-A-G
• rs7302230
• NM_014718.4:c.625A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014718.4(CLSTN3):​c.625A>G​(p.Ser209Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0523 in 1,613,192 control chromosomes in the GnomAD database, including 2,544 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.042 (160 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2384 hom.)
• Consequence: CLSTN3 NM_014718.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• Publications: 15 publications found

Genes affected

CLSTN3 (HGNC:18371): (calsyntenin 3) 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 act upstream of or within several processes, including chemical synaptic transmission; positive regulation of protein localization to synapse; and synapse assembly. Predicted to be located in postsynaptic density. Predicted to be part of protein-containing complex. Predicted to be active in several cellular components, including GABA-ergic synapse; glutamatergic synapse; and postsynaptic membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015180409).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLSTN3	NM_014718.4	c.625A>G	p.Ser209Gly	missense_variant	Exon 5 of 18	ENST00000266546.11	NP_055533.2
CLSTN3	XM_047429919.1	c.868A>G	p.Ser290Gly	missense_variant	Exon 6 of 19		XP_047285875.1
CLSTN3	XM_047429920.1	c.625A>G	p.Ser209Gly	missense_variant	Exon 6 of 19		XP_047285876.1
CLSTN3	XM_047429921.1	c.625A>G	p.Ser209Gly	missense_variant	Exon 6 of 19		XP_047285877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLSTN3	ENST00000266546.11	c.625A>G	p.Ser209Gly	missense_variant	Exon 5 of 18	1	NM_014718.4	ENSP00000266546.6
CLSTN3	ENST00000537408.1	n.1199A>G		non_coding_transcript_exon_variant	Exon 4 of 17	1
CLSTN3	ENST00000540931.1	n.120A>G		non_coding_transcript_exon_variant	Exon 2 of 4	2
CLSTN3	ENST00000541667.5	n.352A>G		non_coding_transcript_exon_variant	Exon 4 of 6	4

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6337 AN: 152166 Hom.: 160 Cov.: 32

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0378

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0560

Gnomad OTH AF: 0.0565

GnomAD2 exomes AF: 0.0418 AC: 10476 AN: 250364 AF XY: 0.0421

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.0295

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0569

Gnomad OTH exome AF: 0.0537

GnomAD4 exome AF: 0.0534 AC: 77963 AN: 1460908 Hom.: 2384 Cov.: 33 AF XY: 0.0523 AC XY: 38040 AN XY: 726756

African (AFR) AF: 0.0189 AC: 633 AN: 33450

American (AMR) AF: 0.0307 AC: 1368 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2735 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0169 AC: 1453 AN: 86192

European-Finnish (FIN) AF: 0.0433 AC: 2312 AN: 53400

Middle Eastern (MID) AF: 0.0609 AC: 351 AN: 5762

European-Non Finnish (NFE) AF: 0.0591 AC: 65709 AN: 1111468

Other (OTH) AF: 0.0564 AC: 3402 AN: 60338

GnomAD4 genome AF: 0.0416 AC: 6335 AN: 152284 Hom.: 160 Cov.: 32 AF XY: 0.0399 AC XY: 2968 AN XY: 74466

African (AFR) AF: 0.0194 AC: 807 AN: 41544

American (AMR) AF: 0.0474 AC: 726 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 369 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4830

European-Finnish (FIN) AF: 0.0378 AC: 401 AN: 10604

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0560 AC: 3812 AN: 68026

Other (OTH) AF: 0.0559 AC: 118 AN: 2112

Alfa AF: 0.0539 Hom.: 1134

Bravo AF: 0.0419

TwinsUK AF: 0.0588 AC: 218

ALSPAC AF: 0.0560 AC: 216

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.0573 AC: 493

ExAC AF: 0.0413 AC: 5012

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0622

EpiControl AF: 0.0683

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.050
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		4.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.094
Sift	Benign	0.74	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.13
MPC		0.24
ClinPred		0.038	T
GERP RS		4.9
Varity_R		0.23
gMVP		0.38
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7302230; hg19: chr12-7288432; COSMIC: COSV56941479; COSMIC: COSV56941479;