1-9730601-C-G

Variant names:

• chr1-9730601-C-G
• rs148584143
• NM_001009566.3:c.2853G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001009566.3(CLSTN1):​c.2853G>C​(p.Glu951Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00797 in 1,610,268 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E951G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (65 hom.)
• Consequence: CLSTN1 NM_001009566.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.953
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058742464).
• BP6: Variant 1-9730601-C-G is Benign according to our data. Variant chr1-9730601-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2638191.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 811 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001009566.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLSTN1	NM_001009566.3	MANE Select	c.2853G>C	p.Glu951Asp	missense	Exon 19 of 19	NP_001009566.1	O94985-1
	CLSTN1	NM_014944.4		c.2823G>C	p.Glu941Asp	missense	Exon 18 of 18	NP_055759.3	O94985-2
	CLSTN1	NM_001302883.1		c.2796G>C	p.Glu932Asp	missense	Exon 18 of 18	NP_001289812.1	O94985

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLSTN1	ENST00000377298.9	TSL:1 MANE Select	c.2853G>C	p.Glu951Asp	missense	Exon 19 of 19	ENSP00000366513.4	O94985-1
	CLSTN1	ENST00000361311.4	TSL:1	c.2823G>C	p.Glu941Asp	missense	Exon 18 of 18	ENSP00000354997.4	O94985-2
	CLSTN1	ENST00000872287.1		c.2859G>C	p.Glu953Asp	missense	Exon 17 of 17	ENSP00000542346.1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 811 AN: 151996 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00538

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00837

Gnomad OTH AF: 0.00914

GnomAD2 exomes AF: 0.00501 AC: 1248 AN: 248872 AF XY: 0.00513

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.00782

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00824 AC: 12016 AN: 1458154 Hom.: 65 Cov.: 31 AF XY: 0.00805 AC XY: 5845 AN XY: 725648

African (AFR) AF: 0.00155 AC: 52 AN: 33480

American (AMR) AF: 0.00400 AC: 179 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00105 AC: 91 AN: 86258

European-Finnish (FIN) AF: 0.00670 AC: 333 AN: 49736

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00983 AC: 10934 AN: 1111982

Other (OTH) AF: 0.00687 AC: 415 AN: 60372

GnomAD4 genome AF: 0.00533 AC: 811 AN: 152114 Hom.: 5 Cov.: 32 AF XY: 0.00502 AC XY: 373 AN XY: 74350

African (AFR) AF: 0.00152 AC: 63 AN: 41520

American (AMR) AF: 0.00537 AC: 82 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4814

European-Finnish (FIN) AF: 0.00613 AC: 65 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00837 AC: 569 AN: 67974

Other (OTH) AF: 0.00905 AC: 19 AN: 2100

Alfa AF: 0.00746 Hom.: 3

Bravo AF: 0.00540

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00480 AC: 583

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00830

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.15	N
PhyloP100		0.95
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.10
Sift	Benign	0.51	T
Sift4G	Benign	0.77	T
Polyphen		0.016	B
Vest4		0.19
MutPred		0.065		Gain of loop (P = 0.1069)
MVP		0.36
MPC		0.27
ClinPred		0.0084	T
GERP RS		2.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.030
gMVP		0.019
Mutation Taster		=100/0	polymorphism

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: rs148584143; hg19: chr1-9790659; COSMIC: COSV63126825; COSMIC: COSV63126825;