1-9730639-C-T

Variant names:

• chr1-9730639-C-T
• rs768841934
• NM_001009566.3:c.2815G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001009566.3(CLSTN1):​c.2815G>A​(p.Gly939Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000807 in 1,610,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: CLSTN1 NM_001009566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17413959).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLSTN1	NM_001009566.3	c.2815G>A	p.Gly939Ser	missense_variant	Exon 19 of 19	ENST00000377298.9	NP_001009566.1
CLSTN1	NM_014944.4	c.2785G>A	p.Gly929Ser	missense_variant	Exon 18 of 18		NP_055759.3
CLSTN1	NM_001302883.1	c.2758G>A	p.Gly920Ser	missense_variant	Exon 18 of 18		NP_001289812.1
CLSTN1	XM_047449470.1	c.2728G>A	p.Gly910Ser	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	c.2815G>A	p.Gly939Ser	missense_variant	Exon 19 of 19	1	NM_001009566.3	ENSP00000366513.4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000806 AC: 20 AN: 248124 Hom.: 0 AF XY: 0.0000520 AC XY: 7 AN XY: 134504

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000257

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000850 AC: 124 AN: 1458396 Hom.: 0 Cov.: 31 AF XY: 0.0000785 AC XY: 57 AN XY: 725694

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000220

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74260

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2815G>A (p.G939S) alteration is located in exon 19 (coding exon 19) of the CLSTN1 gene. This alteration results from a G to A substitution at nucleotide position 2815, causing the glycine (G) at amino acid position 939 to be replaced by a serine (S). 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	0.080
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Benign	0.77
DEOGEN2	Benign	0.019	T;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.63	N;N;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.44
MutPred		0.24		Gain of phosphorylation at G939 (P = 0);.;.;
MVP		0.58
MPC		0.95
ClinPred		0.18	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.075

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: rs768841934; hg19: chr1-9790697;