1-9731352-C-A

Variant names:

• chr1-9731352-C-A
• rs778399511
• NM_001009566.3:c.2602G>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001009566.3(CLSTN1):​c.2602G>T​(p.Val868Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,880 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: 0.0000062 (0 hom.)
• Consequence: CLSTN1 NM_001009566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02

Genes affected

CLSTN1 (HGNC:17447): (calsyntenin 1) This gene is a member of the calsyntenin family, a subset of the cadherin superfamily. The encoded transmembrane protein, also known as alcadein-alpha, is thought to bind to kinesin-1 motors to mediate the axonal anterograde transport of certain types of vesicle. Amyloid precursor protein (APP) is trafficked via these vesicles and so this protein is being investigated to see how it might contribute to the mechanisms underlying Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLSTN1	NM_001009566.3	c.2602G>T	p.Val868Phe	missense_variant	Exon 18 of 19	ENST00000377298.9	NP_001009566.1
CLSTN1	NM_014944.4	c.2572G>T	p.Val858Phe	missense_variant	Exon 17 of 18		NP_055759.3
CLSTN1	NM_001302883.1	c.2545G>T	p.Val849Phe	missense_variant	Exon 17 of 18		NP_001289812.1
CLSTN1	XM_047449470.1	c.2515G>T	p.Val839Phe	missense_variant	Exon 16 of 17		XP_047305426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLSTN1	ENST00000377298.9	c.2602G>T	p.Val868Phe	missense_variant	Exon 18 of 19	1	NM_001009566.3	ENSP00000366513.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251402 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2602G>T (p.V868F) alteration is located in exon 18 (coding exon 18) of the CLSTN1 gene. This alteration results from a G to T substitution at nucleotide position 2602, causing the valine (V) at amino acid position 868 to be replaced by a phenylalanine (F). 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.92
MutPred		0.31		Gain of sheet (P = 0.1208);.;.;
MVP		0.53
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs778399511; hg19: chr1-9791410;