Genetic Variant CLSTN1:p.Thr978Ile (chr1-9730521-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001009566.3(CLSTN1):c.2933C>T(p.Thr978Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CLSTN1
NM_001009566.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.36

Variant links:

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]

CLSTN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
CLSTN1	NM_001009566.3 link	c.2933C>T	p.Thr978Ile	missense_variant	Exon 19 of 19	ENST00000377298.9	NP_001009566.1	O94985-1
CLSTN1	NM_014944.4 link	c.2903C>T	p.Thr968Ile	missense_variant	Exon 18 of 18		NP_055759.3	O94985-2
CLSTN1	NM_001302883.1 link	c.2876C>T	p.Thr959Ile	missense_variant	Exon 18 of 18		NP_001289812.1	O94985B4E3Q1
CLSTN1	XM_047449470.1 link	c.2846C>T	p.Thr949Ile	missense_variant	Exon 17 of 17		XP_047305426.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLSTN1	ENST00000377298.9 link	c.2933C>T	p.Thr978Ile	missense_variant	Exon 19 of 19	1	NM_001009566.3	ENSP00000366513.4		O94985-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1452058

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111664

Other (OTH)

AF:

0.00

AC:

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2933C>T (p.T978I) alteration is located in exon 19 (coding exon 19) of the CLSTN1 gene. This alteration results from a C to T substitution at nucleotide position 2933, causing the threonine (T) at amino acid position 978 to be replaced by an isoleucine (I). 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

0.76

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.085

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Uncertain

2.6

M;.;.

PhyloP100

9.4

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.0

D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.72

MutPred

0.18

Loss of phosphorylation at T978 (P = 0.0316);.;.;

MVP

0.52

MPC

0.99

ClinPred

0.98

GERP RS

5.5

Varity_R

0.45

gMVP

0.11

Mutation Taster

=52/48

polymorphism

(source)

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

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1-9730521-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over